Beta-lactamase inhibitors and uses thereof

ABSTRACT

β-Lactamase inhibiting compounds, therapeutic methods of using the β-lactamase inhibiting compounds, particularly in combination with β-lactam antibiotics and pharmaceutical compositions thereof are disclosed. The β-lactamase inhibiting compounds are suitable for oral administration.

This application is a continuation of U.S. application Ser. No.16/654,281, filed on Oct. 16, 2019, now allowed; which is a continuationof U.S. application Ser. No. 16/116,489, filed on Aug. 29, 2018, whichissued as U.S. Pat. No. 10,500,211; which is a continuation of U.S.application Ser. No. 15/934,497, filed on Mar. 23, 2018, which issued asU.S. Pat. No. 10,085,999; which claims the benefit under 35 U.S. §119(e) to U.S. Provisional Application No. 62/551,043, filed on Aug. 28,2017, and U.S. Provisional Application No. 62/504,523, filed on May 10,2017, each of which is incorporated by reference in its entirety.

FIELD

The present disclosure relates to β-lactamase inhibitors andpharmaceutical compositions thereof and the use of the β-lactamaseinhibitors to treat bacterial infections.

BACKGROUND

Overuse, incorrect use, and agricultural use of antibiotics has led tothe emergence of resistant bacteria that are refractory to eradicationby conventional anti-infective agents, such as those based on β-lactamsor fluoroquinolone architectures. Alarmingly, many of these resistantbacteria are responsible for common infections including, for example,pneumonia, sepsis, etc.

Development of resistance to commonly used β-lactam anti-infectives isrelated to expression of β-lactamases by the targeted bacteria.β-Lactamases typically hydrolyze the β-lactam ring, thus rendering theantibiotic ineffective against bacteria. Accordingly, inhibition ofβ-lactamases by a suitable substrate can prevent degradation of theβ-lactam antibiotic, thereby increasing the effectiveness of theadministered antibiotic and mitigating the emergence of resistance.

Avibactam is a known β-lactamase inhibitor that is currently marketed incombination with ceftazidime to treat gram negative bacterialinfections. Avibactam must be administered intravenously, which limitsuse to expensive clinical settings.

SUMMARY

According to the present invention, compounds have the structure ofFormula (1):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂;wherein,

R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈cycloalkyl, C₅₋₈ heterocycloalkyl, C₅-C₁₀ cycloalkylalkyl, C₅₋₁₀heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀ arylalkyl,C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈heteroalkyl, substituted C₅₋₈ cycloalkyl, substituted C₅₋₈heterocycloalkyl, substituted C₅-C₁₀ cycloalkylalkyl, substituted C₅₋₁₀heterocycloalkylalkyl, substituted C₆₋₈ aryl, substituted C₅₋₈heteroaryl, substituted C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

A is a single bond (—) and R⁷ is hydrogen, or A is a double bond (═) andR⁷ is C₁₋₃ alkyl.

According to the present invention, pharmaceutical compositions comprisethe compound according to the present invention and a pharmaceuticallyacceptable vehicle.

According to the present invention, methods of treating a bacterialinfection in a patient comprise administering to a patient in need ofsuch treatment a therapeutically effective amount of the compoundaccording to the present invention.

According to the present invention, methods of treating a bacterialinfection in a patient comprise administering to a patient in need ofsuch treatment a therapeutically effective amount of the pharmaceuticalcomposition according to the present invention.

According to the present invention, methods of inhibiting a β-lactamasein a patient comprise administering to the patient an effective amountof the compound according to the present invention.

According to the present invention, methods of inhibiting a β-lactamasein a patient comprise administering to the patient an effective amountof the pharmaceutical composition according to the present invention.

Reference is now made to certain compounds and methods. The disclosedembodiments are not intended to be limiting of the claims. To thecontrary, the claims are intended to cover all alternatives,modifications, and equivalents.

DETAILED DESCRIPTION

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,—CONH₂ is attached through the carbon atom.

“Alkyl” refers to a saturated or unsaturated, branched, orstraight-chain, monovalent hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent alkane, alkene,or alkyne. Examples of alkyl groups include methyl; ethyls such asethanyl, ethenyl, and ethynyl; propyls such as propan-1-yl, propan-2-yl,prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, but-1-en-1-yl,but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl,but-3-yn-1-yl, etc.; and the like. The term “alkyl” is specificallyintended to include groups having any degree or level of saturation,i.e., groups having exclusively carbon-carbon single bonds, groupshaving one or more carbon-carbon double bonds, groups having one or morecarbon-carbon triple bonds, and groups having combinations ofcarbon-carbon single, double, and triple bonds. Where a specific levelof saturation is intended, the terms alkanyl, alkenyl, and alkynyl areused. An alkyl group can be C₁₋₆ alkyl, C₁_₅ alkyl, C₁₄ alkyl, C₁₋₃alkyl, ethyl or methyl.

“Alkoxy” refers to a radical —OR where R is alkyl as defined herein.Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy.An alkoxy group can be C₁₋₆ alkoxy, C₁₋₅ alkoxy, C₁₋₄ alkoxy, C₁₋₃alkoxy, ethoxy, or methoxy.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem. Aryl encompasses 5- and 6-membered carbocyclic aromatic rings,for example, benzene; bicyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, naphthalene, indane, andtetralin; and tricyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, fluorene. Aryl encompassesmultiple ring systems having at least one carbocyclic aromatic ringfused to at least one carbocyclic aromatic ring, cycloalkyl ring, orheterocycloalkyl ring. For example, aryl includes a phenyl ring fused toa 5- to 7-membered heterocycloalkyl ring containing one or moreheteroatoms selected from N, O, and S. For such fused, bicyclic ringsystems wherein only one of the rings is a carbocyclic aromatic ring,the radical carbon atom may be at the carbocyclic aromatic ring or atthe heterocycloalkyl ring. Examples of aryl groups include groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene, and the like. An aryl group can be C₆₋₁₀ aryl, C₆₋₉aryl, C₆₋₈ aryl, or phenyl. Aryl, however, does not encompass or overlapin any way with heteroaryl, separately defined herein.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom is replaced with an aryl group.Examples of arylalkyl groups include benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, and 2-naphthophenylethan-1-yl.Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl, or arylalkynyl is used. An arylalkyl group canbe C₇₋₁₆ arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is C₁₋₆ and the aryl moiety is C₆₋₁₀. An arylalkyl groupcan be C₇₋₁₆ arylalkyl, such as the alkanyl, alkenyl or alkynyl moietyof the arylalkyl group is C₁₋₆ and the aryl moiety is C₆₋₁₀. Anarylalkyl group can be C₇₋₉ arylalkyl, wherein the alkyl moiety is C₁₋₃alkyl and the aryl moiety is phenyl. An arylalkyl group can be C₇₋₁₆arylalkyl, C₇₋₁₄ arylalkyl, C₇₋₁₂ arylalkyl, C₇₋₁₀ arylalkyl, C₇₋₈arylalkyl, or benzyl.

“Bioavailability” refers to the rate and amount of a drug that reachesthe systemic circulation of a patient following administration of thedrug or prodrug thereof to the patient and can be determined byevaluating, for example, the plasma or blood concentration-versus-timeprofile for a drug. Parameters useful in characterizing a plasma orblood concentration-versus-time curve include the area under the curve(AUC), the time to maximum concentration (T_(max)), and the maximum drugconcentration (C_(max)), where C_(max) is the maximum concentration of adrug in the plasma or blood of a patient following administration of adose of the drug or form of drug to the patient, and T_(max) is the timeto the maximum concentration (C_(max)) of a drug in the plasma or bloodof a patient following administration of a dose of the drug or form ofdrug to the patient.

“Oral bioavailability” (F %) refers to the fraction of an oraladministered drug that reaches systemic circulation. Oralbioavailability is a product of the fraction absorbed, the fractionescaping gut-wall elimination, and the fraction escaping hepaticelimination; and the factors that influence bioavailability can bedivided into physiological, physicochemical, and biopharmaceuticalfactors.

“Compounds” and moieties disclosed herein include any specific compoundswithin these formulae. Compounds may be identified either by theirchemical structure and/or chemical name. Compounds are named using theChemBioDraw Ultra Version 14.0.0.117 (CambridgeSoft, Cambridge, Mass.)nomenclature/structure program. When the chemical structure and chemicalname conflict, the chemical structure is determinative of the identityof the compound. The compounds described herein may comprise one or morestereogenic centers and/or double bonds and therefore may exist asstereoisomers such as double-bond isomers (i.e., geometric isomers),enantiomers, diastereomers, or atropisomers. Accordingly, any chemicalstructures within the scope of the specification depicted, in whole orin part, with a relative configuration encompass all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure, or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures may be resolved intotheir component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled artisan.

Compounds and moieties disclosed herein include optical isomers ofcompounds and moieties, racemates thereof, and other mixtures thereof.In such embodiments, the single enantiomers or diastereomers may beobtained by asymmetric synthesis or by resolution of the racemates.Resolution of the racemates may be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column with chiral stationaryphases. In addition, compounds include (Z)- and (E)-forms (or cis- andtrans-forms) of compounds with double bonds either as single geometricisomers or mixtures thereof.

Compounds and moieties may also exist in several tautomeric formsincluding the enol form, the keto form, and mixtures thereof.Accordingly, the chemical structures depicted herein encompass allpossible tautomeric forms of the illustrated compounds. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms. Certain compounds may exist in multiple crystalline,co-crystalline, or amorphous forms. Compounds include pharmaceuticallyacceptable salts thereof, or pharmaceutically acceptable solvates of thefree acid form of any of the foregoing, as well as crystalline forms ofany of the foregoing

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylradical. A cycloalkyl group can beC₃₋₆ cycloalkyl, C₃₋₅ cycloalkyl, C₅₋₆cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl. A cycloalkyl can beselected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Cycloalkylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom is replaced with a cycloalkylgroup as defined herein. Where specific alkyl moieties are intended, thenomenclature cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl isused. A cycloalkylalkyl group can be C₄₋₃₀ cycloalkylalkyl, for example,the alkanyl, alkenyl, or alkynyl moiety of the cycloalkylalkyl group isC₁₋₁₀ and the cycloalkyl moiety of the cycloalkylalkyl moiety is C₃-20.A cycloalkylalkyl group can be C₄₋₂₀ cycloalkylalkyl for example, thealkanyl, alkenyl, or alkynyl moiety of the cycloalkylalkyl group is C₁₋₈and the cycloalkyl moiety of the cycloalkylalkyl group is C₃₋₁₂. Acycloalkylalkyl can be C₄₋₉ cycloalkylalkyl, wherein the alkyl moiety ofthe cycloalkylalkyl group is C₁₋₃ alkyl, and the cycloalkyl moiety ofthe cycloalkylalkyl group is C₃₋₆ cycloalkyl. A cycloalkylalkyl groupcan be C₄₋₁₂ cycloalkylalkyl, C₄₋₁₀ cycloalkylalkyl, C₄₋₈cycloalkylalkyl, and C₄₋₆ cycloalkylalkyl. A cycloalkylalkyl group canbe cyclopropylmethyl (—CH₂-cyclo-C₃H₅), cyclopentylmethyl(—CH₂-cyclo-C₅H₉), or cyclohexylmethyl (—CH₂-cyclo-C₆H₁₁). Acycloalkylalkyl group can be cyclopropylethenyl (—CH═CH-cyclo-C₃H₅), orcyclopentylethynyl (—C—C-cyclo-C₅H₉).

“Cycloalkylheteroalkyl” by itself or as part of another substituentrefers to a heteroalkyl group in which one or more of the carbon atoms(and certain associated hydrogen atoms) of an alkyl group areindependently replaced with the same or different heteroatomic group orgroups and in which one of the hydrogen atoms bonded to a carbon atom isreplaced with a cycloalkyl group. Where specific alkyl moieties areintended, the nomenclature cycloalkylheteroalkanyl,cycloalkylheteroalkenyl, and cycloalkylheteroalkynyl is used. In acycloalkylheteroalkyl, the heteroatomic group can be selected from —O—,—S—, —NH—, —N(—CH₃)—, —SO—, and —SO₂—, or the heteroatomic group can beselected from —O— and —NH—, or the heteroatomic group is —O— or —NH—.

“Cycloalkyloxy” refers to a radical —OR where R is cycloalkyl as definedherein. Examples of cycloalkyloxy groups include cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. A cycloalkyloxy groupcan be C₃₋₆ cycloalkyloxy, C₃₋₅ cycloalkyloxy, C₅₋₆ cycloalkyloxy,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

“Disease” refers to a disease, disorder, condition, or symptom of any ofthe foregoing.

“Fluoroalkyl” refers to an alkyl group as defined herein in which one ormore of the hydrogen atoms is replaced with a fluoro. A fluoroalkylgroup can be C₁₋₆ fluoroalkyl, C₁₋₅ fluoroalkyl, C₁₄ fluoroalkyl, orC₁₋₃ fluoroalkyl. A fluoroalkyl group can be pentafluoroethyl (—CF₂CF₃),or trifluoromethyl (—CF₃).

“Fluoroalkoxy” refers to an alkoxy group as defined herein in which oneor more of the hydrogen atoms is replaced with a fluoro. A fluoroalkoxygroup can be C₁₋₆ fluoroalkoxy, C₁₋₅ fluoroalkoxy, C₁₋₄ fluoroalkoxyC₁₋₃, fluoroalkoxy, —OCF₂CF₃ or —OCF₃.

“Halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Heteroalkoxy” refers to an alkoxy group in which one or more of thecarbon atoms are replaced with a heteroatom. A heteroalkoxy group can beC₁₋₆ heteroalkoxy, C₁₋₅ heteroalkoxy, C₁₋₄ heteroalkoxy, or C₁₋₃heteroalkoxy. In a heteroalkoxy, the heteroatomic group can be selectedfrom —O—, —S—, —NH—, —NR—, —SO₂—, and —SO₂—, or the heteroatomic groupcan be selected from —O— and —NH—, or the heteroatomic group is —O— and—NH—. A heteroalkoxy group can be C₁₋₆ heteroalkoxy, C₁₋₅ heteroalkoxy,C₁₄ heteroalkoxy, or C₁₋₃ heteroalkoxy.

“Heteroalkyl” by itself or as part of another substituent refer to analkyl group in which one or more of the carbon atoms (and certainassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatomic group or groups. Examples of heteroatomic groupsinclude —O—, —S—, —NH—, —NR—, —O—O—, —S—S—, ═N—N═, —N═N—, —N═N—NR—,—PR—, —P(O)OR—, —P(O)R—, —POR—, —SO—, —SO₂—, —Sn(R)₂—, and the like,where each R is independently selected from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₆₋₁₂ aryl, substituted C₆₋₁₂ aryl, C₇₋₁₈arylalkyl, substituted C₇₋₁₈ arylalkyl, C₃₋₇ cycloalkyl, substitutedC₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, substituted C₃₋₇heterocycloalkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl,C₆₋₁₂heteroaryl, substituted C₆₋₁₂ heteroaryl, C₇₋₁₈ heteroarylalkyl,and substituted C₇₋₁₈ heteroarylalkyl. Each R can be independentlyselected from hydrogen and C₁₋₃ alkyl. Reference to, for example, a C₁₋₆heteroalkyl, means a C₁₋₆ alkyl group in which at least one of thecarbon atoms (and certain associated hydrogen atoms) is replaced with aheteroatom. For example, C₁₋₆ heteroalkyl includes groups having fivecarbon atoms and one heteroatom, groups having four carbon atoms and twoheteroatoms, etc. In a heteroalkyl, the heteroatomic group can beselected from —O—, —S—, —NH—, —N(—CH₃)—, —SO—, and —SO₂—, or theheteroatomic group can be selected from —O— and —NH—, or theheteroatomic group can be —O— or —NH—. A heteroalkyl group can be C₁₋₆heteroalkyl, C₁₋₅ heteroalkyl, or C₁₋₄ heteroalkyl, or C₁₋₃ heteroalkyl.

“Heteroaryl” by itself or as part of another substituent refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring system.Heteroaryl encompasses multiple ring systems having at least oneheteroaromatic ring fused to at least one other ring, which may bearomatic or non-aromatic. For example, heteroaryl encompasses bicyclicrings in which one ring is heteroaromatic and the second ring is aheterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systemswherein only one of the rings contains one or more heteroatoms, theradical carbon may be at the aromatic ring or at the heterocycloalkylring. When the total number of N, S, and O atoms in the heteroaryl groupexceeds one, the heteroatoms may or may not be adjacent to one another.The total number of heteroatoms in the heteroaryl group is not more thantwo. In a heteroaryl, the heteroatomic group can be selected from —O—,—S—, —NH—, —N(—CH₃)—, —S(O)—, and —SO₂—, or the heteroatomic group canbe selected from —O— and —NH—, or the heteroatomic group can be —O— or—NH—. A heteroaryl group can be selected from C₅₋₁₀ heteroaryl, C₅₋₉heteroaryl, C₅₋₈ heteroaryl, C₅₋₇ heteroaryl, C₅₋₆ heteroaryl, C₅heteroaryl or C₆ heteroaryl.

Examples of suitable heteroaryl groups include groups derived fromacridine, arsindole, carbazole, α-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,thiazolidine, oxazolidine, and the like. A heteroaryl group can bederived from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole, or pyrazine. For example, aheteroaryl can be C₅ heteroaryl and can be selected from furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, or isoxazolyl. Aheteroaryl can be C₆ heteroaryl, and can be selected from pyridinyl,pyrazinyl, pyrimidinyl, and pyridazinyl.

“Heteroarylalkyl” refers to an arylalkyl group in which one of thecarbon atoms (and certain associated hydrogen atoms) is replaced with aheteroatom. A heteroarylalkyl group can be C₆₋₁₆ heteroarylalkyl, C₆₋₁₄heteroarylalkyl, C₆₋₁₂ heteroarylalkyl, C₆₋₁₀ heteroarylalkyl, C₆₋₈heteroarylalkyl, or C₇ heteroarylalkyl, or C₆ heteroarylalkyl. In aheteroarylalkyl, the heteroatomic group can be selected from —O—, —S—,—NH—, —N(—CH₃)—, —SO—, and —SO₂—, or the heteroatomic group can beselected from —O— and —NH—, or the heteroatomic group can be —O— or—NH—.

“Heterocycloalkyl” by itself or as part of another substituent refers toa saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and certain associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom; or to a parent aromaticring system in which one or more carbon atoms (and certain associatedhydrogen atoms) are independently replaced with the same or differentheteroatom such that the ring system violates the Hückel-rule. Examplesof heteroatoms to replace the carbon atom(s) include N, P, O, S, and Si.Examples of heterocycloalkyl groups include groups derived fromepoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, and quinuclidine. Aheterocycloalkyl can be C₅ heterocycloalkyl and is selected frompyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl,oxazolidinyl, thiazolidinyl, doxolanyl, and dithiolanyl. Aheterocycloalkyl can be C₆ heterocycloalkyl and can be selected frompiperidinyl, tetrahydropyranyl, piperizinyl, oxazinyl, dithianyl, anddioxanyl. A heterocycloalkyl group can be C₃₋₆ heterocycloalkyl, C₃₋₅heterocycloalkyl, C₅₋₆ heterocycloalkyl, C₅ heterocycloalkyl or C₆heterocycloalkyl. In a heterocycloalkyl, the heteroatomic group can beselected from —O—, —S—, —NH—, —N(—CH₃)—, —SO—, and —SO₂—, or theheteroatomic group can be selected from —O— and —NH—, or theheteroatomic group can be —O— or —NH—.

“Heterocycloalkylalkyl” refers to a cycloalkylalkyl group in which oneor more carbon atoms (and certain associated hydrogen atoms) of thecycloalkyl ring are independently replaced with the same or differentheteroatom. A heterocycloalkylalkyl can be C₄₋₁₂ heterocycloalkylalkyl,C₄₋₁₀ heterocycloalkylalkyl, C₄₋₈ heterocycloalkylalkyl, C₄₋₆heterocycloalkylalkyl, C₆₋₇ heterocycloalkylalkyl, or C₆heterocycloalkylalkyl or C₇ heterocycloalkylalkyl. In aheterocycloalkylalkyl, the heteroatomic group can be selected from —O—,—S—, —NH—, —N(—CH₃)—, —SO—, and —SO₂—, or the heteroatomic group can beselected from —O— and —NH—, or the heteroatomic group can be —O— or—NH—.

“Parent aromatic ring system” refers to an unsaturated cyclic orpolycyclic ring system having a cyclic conjugated it (pi) electronsystem with 4n+2 electrons (Hückel rule). Included within the definitionof “parent aromatic ring system” are fused ring systems in which one ormore of the rings are aromatic and one or more of the rings aresaturated or unsaturated, such as, for example, fluorene, indane,indene, phenalene, etc. Examples of parent aromatic ring systems includeaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene,and the like.

“Hydrates” refers to incorporation of water into to the crystal latticeof a compound described herein, in stoichiometric proportions, resultingin the formation of an adduct. Methods of making hydrates include, butare not limited to, storage in an atmosphere containing water vapor,dosage forms that include water, or routine pharmaceutical processingsteps such as, for example, crystallization (i.e., from water or mixedaqueous solvents), lyophilization, wet granulation, aqueous filmcoating, or spray drying. Hydrates may also be formed, under certaincircumstances, from crystalline solvates upon exposure to water vapor,or upon suspension of the anhydrous material in water. Hydrates may alsocrystallize in more than one form resulting in hydrate polymorphism.

“Metabolic intermediate” refers to a compound that is formed in vivo bymetabolism of a parent compound and that further undergoes reaction invivo to release an active agent. Compounds of Formula (1) are protectedsulfonate nucleophile prodrugs of non-β-lactam β-lactamase inhibitorsthat are metabolized in vivo to provide the corresponding metabolicintermediates such as avibactam ([2S,SR]-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogensulfate). Metabolic intermediates undergo nucleophilic cyclization torelease a non-β-lactam β-lactamase inhibitor such as avibactam and oneor more reaction products. It is desirable that the reaction products ormetabolites thereof not be toxic.

“Neopentyl” refers to a radical in which a methylene carbon is bonded toa carbon atom, which is bonded to three non-hydrogen substituents.Examples of non-hydrogen substituents include carbon, oxygen, nitrogen,and sulfur. Each of the three non-hydrogen substituents can be carbon.Two of the three non-hydrogen substituents can be carbon, and the thirdnon-hydrogen substituent can be selected from oxygen and nitrogen. Aneopentyl group can have the structure:

where each R¹ is defined as for Formula (1).

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated it electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Examples ofparent aromatic ring systems include aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, and trinaphthalene.

“Parent heteroaromatic ring system” refers to an aromatic ring system inwhich one or more carbon atoms (and any associated hydrogen atoms) areindependently replaced with the same or different heteroatom in such away as to maintain the continuous it-electron system characteristic ofaromatic systems and a number of π-electrons corresponding to the Hückelrule (4n+2). Examples of heteroatoms to replace the carbon atoms includeN, P, O, S, and Si, etc. Specifically included within the definition of“parent heteroaromatic ring systems” are fused ring systems in which oneor more of the rings are aromatic and one or more of the rings aresaturated or unsaturated, such as, for example, arsindole, benzodioxan,benzofuran, chromane, chromene, indole, indoline, and xanthene. Examplesof parent heteroaromatic ring systems include arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, thiazolidine, and oxazolidine.

“Patient” refers to a mammal, for example, a human. The term “patient”is used interchangeably with “subject.”

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include acid addition salts, formed with inorganic acids andone or more protonable functional groups such as primary, secondary, ortertiary amines within the parent compound. Examples of inorganic acidsinclude hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. A salt can be formed with organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like. A salt can be formed when one or more acidic protons presentin the parent compound are replaced by a metal ion, such as an alkalimetal ion, an alkaline earth ion, or an aluminum ion, or combinationsthereof; or coordinates with an organic base such as ethanolamine,diethanolamine, triethanolamine, and N-methylglucamine. Apharmaceutically acceptable salt can be the hydrochloride salt. Apharmaceutically acceptable salt can be the sodium salt. In compoundshaving two or more ionizable groups, a pharmaceutically acceptable saltcan comprise one or more counterions, such as a bi-salt, for example, adihydrochloride salt.

The term “pharmaceutically acceptable salt” includes hydrates and othersolvates, as well as salts in crystalline or non-crystalline form. Wherea particular pharmaceutically acceptable salt is disclosed, it isunderstood that the particular salt such as a hydrochloride salt, is anexample of a salt, and that other salts may be formed using techniquesknown to one of skill in the art. Additionally, one of skill in the artwould be able to convert the pharmaceutically acceptable salt to thecorresponding compound, free base and/or free acid, using techniquesgenerally known in the art.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which a compoundprovided by the present disclosure may be administered to a patient andwhich does not destroy the pharmacological activity thereof and which isnon-toxic when administered in doses sufficient to provide atherapeutically effective amount of the compound.

“Pharmaceutical composition” refers to a compound of Formula (1) or apharmaceutically acceptable salt thereof and at least onepharmaceutically acceptable vehicle, with which the compound of Formula(1) or a pharmaceutically acceptable salt thereof is administered to apatient. Pharmaceutically acceptable vehicles are known in the art.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease). In some embodiments, “preventing” or“prevention” refers to reducing symptoms of the disease by taking thecompound in a preventative fashion. The application of a therapeutic forpreventing or prevention of a disease of disorder is known asprophylaxis. Compounds provided by the present disclosure can providesuperior prophylaxis because of lower long-term side effects over longtime periods.

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently, although not necessarily, pharmacologically inactive untilconverted to the parent drug.

“Promoiety” refers to a group bonded to a drug, typically to afunctional group of the drug, via bond(s) that are cleavable underspecified conditions of use. The bond(s) between the drug and promoietymay be cleaved by enzymatic or non-enzymatic means. Under the conditionsof use, for example following administration to a patient, the bond(s)between the drug and promoiety may be cleaved to release the parentdrug. The cleavage of the promoiety may proceed spontaneously, such asvia a hydrolysis reaction, or it may be catalyzed or induced by anotheragent, such as by an enzyme, by light, by acid, or by a change of orexposure to a physical or environmental parameter, such as a change oftemperature, pH, etc. The agent may be endogenous to the conditions ofuse, such as an enzyme present in the systemic circulation of a patientto which the prodrug is administered or the acidic conditions of thestomach or the agent may be supplied exogenously. For example, for acompound of Formula (1), the promoiety can have the structure:

where R¹, R², and R³ are defined as for Formula (1).

“Single bond” as in the expression “R² is selected from a single bond”refers to a moiety in which R² is a single bond. For example, in amoiety having the structure —C(R¹)₂—R²—R³, where R² is a single bond,—R²— corresponds to a single bond, “—”, and the moiety has the structure—C(R)₂—R³.

Solvate” refers to a molecular complex of a compound with one or moresolvent molecules in a stoichiometric or non-stoichiometric amount. Suchsolvent molecules are those commonly used in the pharmaceutical arts,which are known to be innocuous to a patient, such as water, ethanol,and the like. A molecular complex of a compound or moiety of a compoundand a solvent can be stabilized by non-covalent intra-molecular forcessuch as, for example, electrostatic forces, van der Waals forces, orhydrogen bonds. The term “hydrate” refers to a solvate in which the oneor more solvent molecules is water.

“Solvates” refers to incorporation of solvents into to the crystallattice of a compound described herein, in stoichiometric proportions,resulting in the formation of an adduct. Methods of making solvatesinclude, but are not limited to, storage in an atmosphere containing asolvent, dosage forms that include the solvent, or routinepharmaceutical processing steps such as, for example, crystallization(i.e., from solvent or mixed solvents) vapor diffusion. Solvates mayalso be formed, under certain circumstances, from other crystallinesolvates or hydrates upon exposure to the solvent or upon suspensionmaterial in solvent. Solvates may crystallize in more than one formresulting in solvate polymorphism.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or different substituent(s). Eachsubstituent can be independently selected from deuterio, halogen, —OH,—CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆ alkoxy, C₁₋₆ alkyl, —COOR, —NR₂, and—CONR₂; wherein each R is independently selected from hydrogen and C₁₋₆alkyl. Each substituent can be independently selected from deuterio,halogen, —NH₂, —OH, C₁₋₃ alkoxy, and C₁₋₃ alkyl, trifluoromethoxy, andtrifluoromethyl. Each substituent can be independently selected fromdeuterio, —OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, andtrifluoromethoxy. Each substituent can be selected from deuterio, C₁₋₃alkyl, ═O, C₁₋₃ alkyl, C₁₋₃ alkoxy, and phenyl. Each substituent can beselected from deuterio, —OH, —NH₂, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

“Treating” or “treatment” of a disease refers to arresting orameliorating a disease or at least one of the clinical symptoms of adisease or disorder, reducing the risk of acquiring a disease or atleast one of the clinical symptoms of a disease, reducing thedevelopment of a disease or at least one of the clinical symptoms of thedisease or reducing the risk of developing a disease or at least one ofthe clinical symptoms of a disease. “Treating” or “treatment” alsorefers to inhibiting the disease, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, and to inhibiting atleast one physical parameter or manifestation that may or may not bediscernible to the patient. “Treating” or “treatment” also refers todelaying the onset of the disease or at least one or more symptomsthereof in a patient who may be exposed to or predisposed to a diseaseor disorder even though that patient does not yet experience or displaysymptoms of the disease.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to affect suchtreatment of the disease or symptom thereof. The “therapeuticallyeffective amount” may vary depending, for example, on the compound, thedisease and/or symptoms of the disease, severity of the disease and/orsymptoms of the disease or disorder, the age, weight, and/or health ofthe patient to be treated, and the judgment of the prescribingphysician. An appropriate amount in any given instance may beascertained by those skilled in the art or capable of determination byroutine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toaffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending, for example, on the compound, the diseaseand its severity and the age, weight, adsorption, distribution,metabolism and excretion, of the patient to be treated.

“Vehicle” refers to a diluent, excipient or carrier with which acompound is administered to a subject. In some embodiments, the vehicleis pharmaceutically acceptable.

Reference is now made in detail to certain embodiments of compounds,compositions, and methods. The disclosed embodiments are not intended tobe limiting of the claims. To the contrary, the claims are intended tocover all alternatives, modifications, and equivalents.

Compounds provided by the present disclosure are sulfonate esterprodrugs of non-β-lactam β-lactamase inhibitors. In the non-β-lactamβ-lactamase inhibitor prodrugs a nucleophilic moiety is positionedproximate to the hydrogen sulfate group. In vivo, the nucleophilicmoiety reacts to release the non-β-lactam β-lactamase inhibitor.Examples of non-β-lactam β-lactamase inhibitors include avibactam([2S,5R]-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogensulfate), relebactam((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-ylhydrogen sulfate), and nacubactam(1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylhydrogen sulfate, and derivatives and analogs of any of the foregoing.These compounds are inhibitors of class A, class C, and certain Class Dβ-lactamases and are useful in the treatment of bacterial infectionswhen used in conjunction with β-lactam antibiotics.

Compounds provided by the present disclosure include compounds ofFormula (1):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈cycloalkyl, C₅₋₈ heterocycloalkyl, C₅-C₁₀ cycloalkylalkyl, C₅₋₁₀heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀ arylalkyl,C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈heteroalkyl, substituted C₅₋₈ cycloalkyl, substituted C₅₋₈heterocycloalkyl, substituted C₅₋₁₀ cycloalkylalkyl, substituted C₅₋₁₀heterocycloalkylalkyl, substituted C₆₋₈ aryl, substituted C₅₋₈heteroaryl, substituted C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

A is a single bond (—) and R⁷ is hydrogen, or A is a double bond (═) andR⁷ is C₁₋₃ alkyl.

In compounds of Formula (1), each substituent can be independentlyselected from deuterio, —OH, —CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆ alkoxy,C₁₋₆ alkyl, —COOR, —NR₂, and —CONR₂; wherein each R is independentlyselected from hydrogen and C₁₋₆ alkyl, such has methyl, ethyl, n-propyl,isopropyl, n-butyl, tert-butyl, or iso-butyl.

In compounds of Formula (1), a substituent group can be a nucleophilicgroup. Nucleophilic groups are functional group having a reactive pairof electrons and having the ability of forming a chemical bond bydonating electrons. Examples of suitable nucleophilic groups includeesters, carboxylates, sulfonates, substituted or unsubstituted amines,alcohols (hydroxyl), thiols, sulfides, hydroxylamines, and imines. Otherexamples of suitable nucleophilic groups include —OH, —CF₃, —O—CF₃,—NO₂, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴,—NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴,—O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴),where each R⁴ is independently selected from hydrogen, C₁₋₆ alkyl, C₁₋₆heteroalkyl, C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀cycloalkylalkyl, C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₆₋₈heteroaryl, C₅₋₁₀ arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₆alkyl, substituted C₁₋₆ heteroalkyl, substituted C₅₋₈ cycloalkyl,substituted C₅₋₈ heterocycloalkyl, substituted C₅-C₁₀ cycloalkylalkyl,substituted C₅₋₁₀ heterocycloalkylalkyl, substituted C₆₋₈ aryl,substituted C₆₋₈ heteroaryl, substituted C₅₋₁₀ arylalkyl, andsubstituted C₅₋₁₀ heteroarylalkyl.

In compounds of Formula (1), each substituent can independently beselected from —OH, —CF₃, —O—CF₃, —NO₂, —O—C(O)—R⁴, —S—C(O)—R⁴,—NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴,—C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴,—S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), wherein each R⁴ is selected fromhydrogen, C₁₋₈ alkyl, and C₁₋₈ heteroalkyl.

In compounds of Formula (1), A can be a single bond (—) and R⁷ can behydrogen.

In compounds of Formula (1), A can be a double bond (═) and R⁷ can beC₁₋₃ alkyl, such as methyl, ethyl, n-propyl, or iso-propyl.

In compounds of Formula (1), each of R⁵ and R⁶ can be hydrogen.

In compounds of Formula (1), A can be a single bond (—); R⁷ can behydrogen; and R⁵ can be hydrogen.

In compounds of Formula (1), A can be a double bond (═) and R⁷ can beC₁₋₃ alkyl, such as methyl, ethyl, n-propyl, or iso-propyl; and each ofR⁵ and R⁶ can be hydrogen.

In compounds of Formula (1), the compound can have the structure ofFormula (2):

In compounds of Formula (1), the compound can have the structure ofFormula (2a):

In compounds of Formula (1), the compound can have the structure ofFormula (3):

In compounds of Formula (1), the compound can have the structure ofFormula (3a):

In compounds of Formula (1), the compound can have the structure ofFormula (4):

In compounds of Formula (1), the compound can have the structure ofFormula (5):

In compounds of Formula (1), R⁵ can be C₂_₆ heteroalkyl comprising aterminal amine group, and R⁶ can be hydrogen. For example, R⁵ can be—O—(CH₂)₂—NH₂, —CH₂—O—CH₂—NH₂, —(CH₂)₂—O—CH₂—NH₂, or —CH₂—O—(CH₂)₂—NH₂.

In compounds of Formula (1), A can be a single bond (—) and R⁷ can behydrogen, R⁵ can be —O—(CH₂)₂—NH₂, and R⁶ can be hydrogen.

In compounds of Formula (1), R⁵ can be C₄₋₆ heterocycloalkyl comprisingat least one —NH— moiety, and R⁶ can be hydrogen. For example, R⁵ can be2-yl-piperidine, 3-yl-piperidine, or 4-yl-piperidine.

In compounds of Formula (1), A can be a single bond (—) and R⁷ can behydrogen, R⁵ can be 4-yl-piperidine, and R⁶ can be hydrogen.

In compounds of Formula (1)-(5), each R¹ can independently be C₁₋₆alkyl.

In compounds of Formula (1)-(5), each R¹ can independently be methyl,ethyl, or n-propyl.

In compounds of Formula (1)-(5), each R¹ can be same and is methyl,ethyl, or n-propyl.

In compounds of Formula (1)-(5), each R¹ is methyl.

In compounds of Formula (1)-(5), each R¹ together with the geminalcarbon atom to which they are bonded can form a C₃₋₆ cycloalkyl ring ora substituted C₃₋₆ cycloalkyl ring.

In compounds of Formula (1)-(5), each R¹ together with the geminalcarbon atom to which they are bonded can form a C₃₋₆ cycloalkyl ring.For example, each R¹ together with the geminal carbon atom to which theyare bonded can form a cyclopropyl ring, a cyclobutyl ring, a cyclopentylring, or a cyclohexyl ring.

compounds of Formula (1)-(5), each R¹ each R¹ together with the geminalcarbon atom to which they are bonded can form a C₃₋₆ heterocycloalkylring or a substituted C₃₋₆ heterocycloalkyl ring.

In compounds of Formula (1)-(5), R² can be selected from a single bond,C₁₋₂ alkanediyl, and substituted C₁₋₂ alkanediyl.

In compounds of Formula (1)-(5), R² can be a single bond.

In compounds of Formula (1)-(5), R² can be a single bond; and R³ can beC₁₋₆ alkyl.

In compounds of Formula (1)-(5), R² can be selected from C₁₋₂ alkanediyland substituted C₁₋₂ alkanediyl.

In compounds of Formula (1)-(5), R² can be methanediyl, ethanediyl,substituted methanediyl, or substituted ethanediyl.

In compounds of Formula (1)-(5), R² can be substituted C₁₋₂ alkanediylwhere the substituted group can be selected from —OH, —CN, —CF₃, —OCF₃,═O, —NO₂, C₁₋₆ alkoxy, C₁₋₆ alkyl, —COOR, —NR₂, and —CONR₂; wherein eachR is independently selected from hydrogen and C₁₋₆ alkyl.

In compounds of Formula (1)-(5), R² can be substituted C₁₋₂ alkanediylwhere the substituent group can be a nucleophilic group. For example, R²can be substituted C₁₋₂ alkanediyl where the substituent group can beselected from —OH, —CF₃, —O—CF₃, —NO₂, —O—C(O)—R⁴, —S—C(O)—R⁴,—NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴,—C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴,—S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), where each R⁴ is defined as forFormula (1), or each R⁴ is selected from hydrogen and C₁₋₈ alkyl.

In compounds of Formula (1)-(5), R² can be substituted C₁₋₂ alkanediylwhere the substituent group is selected from —OH, —O—C(O)—R⁴,—S—C(O)—R⁴, —NH—C(O)—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —S—S—R⁴,—S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), substituted C₅₋₆ aryl, —NHR⁴,—CH(—NH₂)(—R⁴); and R⁴ is defined as for Formula (1), or each R⁴ isselected from hydrogen and C₁₋₈ alkyl.

In compounds of Formula (1)-(5), where R² is substituted C₁₋₆alkanediyl, substituted C₁₋₆ heteroalkanediyl, or substituted C₅₋₆arenediyl, the stereochemistry of the carbon atom to which thesubstituent group is bonded can be of the (S) configuration.

In compounds of Formula (1)-(5), where R² is substituted C₁₋₆alkanediyl, substituted C₁₋₆ heteroalkanediyl, or substituted C₅₋₆arenediyl, the stereochemistry of the carbon atom to which thesubstituent group is bonded can be of the (R) configuration.

In compounds of Formula (1)-(5), R² is selected from C₅₋₆cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₅₋₆ arenediyl, and C₅₋₆heterocycloalkanediyl.

In compounds of Formula (1)-(5), R² can be cyclopenta-1,3-diene-diyl,substituted cyclopenta-1,3-diene-diyl, benzene-diyl or substitutedbenzene-diyl. For example, R² can be 1,2-benzene-diyl or substituted1,2-benzene-diyl.

In compounds of Formula (1)-(5), R³ can be selected from —O—C(O)—R⁴,—S—C(O)—R⁴, —NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴,—C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴,—O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴); where R⁴ isdefined as for Formula (1), or each R⁴ is selected from hydrogen andC₁₋₈ alkyl.

In compounds of Formula (1)-(5), R³ can be selected from —O—C(O)—R⁴,—C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴, —S—S—R⁴, —NH—R⁴, and —CH(—NH₂)(—R⁴);where R⁴ is defined as for Formula (1), or each R⁴ is selected fromhydrogen and C₁₋₈ alkyl.

In compounds of Formula (1)-(5), R³ is —C(O)—O—R⁴); where R⁴ is definedas for Formula (1), or each R⁴ is selected from hydrogen and C₁₋₈ alkyl.

In compounds of Formula (1)-(5), R⁴ can be selected from hydrogen, C₁₋₃alkyl, C₅₋₆ cycloalkyl, C₅₋₆ heterocycloalkyl, C₅₋₆ aryl, substitutedC₁₋₃ alkyl, substituted C₅₋₆ cycloalkyl, substituted C₅₋₆heterocycloalkyl, and substituted C₅₋₆ aryl.

In compounds of Formula (1)-(5), R⁴ can be selected from methyl, ethyl,phenyl, and benzyl.

In compounds of Formula (1)-(5), R⁴ can be selected from hydrogen andC₁₋₈ alkyl.

In compounds of Formula (1)-(5), R⁴ can be selected from C₁₋₈ alkyl,C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, C₅₋₇ heterocycloalkyl, substitutedC₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl, substituted C₇₋₉ arylalkyl,and substituted C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(5), R⁴ can be selected from C₁₋₈ alkyl,C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(5), R⁴ can be selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl,2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl,cyclohexyl, and 2-pyrrolidinyl.

In compounds of Formula (1)-(5), R³ can be —C(O)—O—R⁴; and R⁴ can beselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₇ cycloalkyl, C₅₋₇heterocycloalkyl, C₆ aryl, C₇₋₉ arylalkyl, substituted C₁₋₈ alkyl,substituted C₁₋₈ heteroalkyl, substituted C₅₋₆ cycloalkyl, substitutedC₅₋₆ heterocycloalkyl, substituted C₆ aryl, and C₇₋₉ arylalkyl,

In compounds of Formula (1)-(5), R³ can be —C(O)—O—R⁴; and R⁴ can beselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, C₅₋₇heterocycloalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl,substituted C₇₋₉ arylalkyl, and substituted C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(5), R³ can be —C(O)—O—R⁴; and R⁴ can beselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇heterocycloalkyl.

In compounds of Formula (1)-(5), R³ can be selected from —O—C(O)—CH₃,—O—C(O)—CH₂—CH₃, —O—C(O)-phenyl, —O—C(O)—CH₂-phenyl, —S—C(O)—CH₃,—S—C(O)—CH₂—CH₃, —S—C(O)— phenyl, —S—C(O)—CH₂-phenyl, —NH—C(O)—CH₃,—NH—C(O)—CH₂—CH₃, —NH—C(O)-phenyl, —NH—C(O)—CH₂-phenyl, —O—C(O)—O—CH₃,—O—C(O)—O—CH₂—CH₃, —O—C(O)—O-phenyl, —O—C(O)—O—CH₂-phenyl,—S—C(O)—O—CH₃, —S—C(O)—O—CH₂—CH₃, —S—C(O)—O-phenyl,—S—C(O)—O—CH₂-phenyl, —NH—C(O)—O—CH₃, —NH—C(O)—O—CH₂—CH₃,—NH—C(O)—O-phenyl, —NH—C(O)—O—CH₂-phenyl, —C(O)—O—CH₃, —C(O)—O—CH₂—CH₃,—C(O)—O-phenyl, —C(O)—O—CH₂-phenyl, —C(O)—S—CH₃, —(O)—S—CH₂—CH₃,—C(O)—S-phenyl, —C(O)—S—CH₂-phenyl, —C(O)—NH—CH₃, —C(O)—NH—CH₂—CH₃,—C(O)—NH-phenyl, —C(O)—NH—CH₂-phenyl, —O—C(O)—O—CH₃, —O—C(O)—O—CH₂—CH₃,—O—C(O)—O-phenyl, —O—C(O)—O—CH₂-phenyl, —O—C(O)—S—CH₃,—O—C(O)—S—CH₂—CH₃, —O—C(O)—S-phenyl, —O—C(O)—S—CH₂-phenyl,—O—C(O)—NH—CH₃, —O—C(O)—NH—CH₂—CH₃, —O—C(O)—NH-phenyl,—O—C(O)—NH—CH₂-phenyl, —S—SH, —S—S—CH₃, —S—S—CH₂—CH₃, —S—S-phenyl,—S—S—CH₂-phenyl, —SH, —S—CH₃, —S—CH₂—CH₃, —S-phenyl, —S—CH₂-phenyl,—NH₂, —NH—CH₃, —NH—CH₂—CH₃, —NH-phenyl, —NH—CH₂-phenyl, —CH(—NH₂)(—CH₃),—CH(—NH₂)(—CH₂—CH₃), —CH(—NH₂)(-phenyl), and —CH(—NH₂)(—CH₂-phenyl).

In compounds of Formula (1)-(5), R³ can be selected from C₅₋₆cycloalkyl, C₅₋₆ heterocycloalkyl, C₅₋₆ aryl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, and substituted C₅₋₆ heteroaryl, comprising atleast one nucleophilic group. For example, R³ can have the structure ofFormula (4a) or Formula (4b):

In compounds of Formula (1)-(5), R can be selected from C₁₋₃ alkyl, C₅₋₆cycloalkyl, C₅₋₆ heterocycloalkyl, C₅₋₆ aryl, substituted C₁₋₃ alkyl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl, andsubstituted C₅₋₆ aryl.

In compounds of Formula (1)-(5), each R¹ together with the carbon atomto which they are bonded form a C₄₋₆ heterocycloalkyl ring comprisingtwo adjacent S atoms or a substituted C₄₋₆ heterocycloalkyl ringcomprising at least one heteroatom selected from O and S, and a carbonyl(═O) substituent group bonded to a carbon atom adjacent the at least oneheteroatom.

In compounds of Formula (1)-(5), R² can be a bond; R³ can be C₁₋₃ alkyl;and each R¹ together with the carbon atom to which they are bonded forma C₄₋₆ heterocycloalkyl ring comprising two adjacent S atoms or asubstituted C₄₋₆ heterocycloalkyl ring comprising at least oneheteroatom selected from O and S, and a═O substituent group bonded to acarbon atom adjacent the heteroatom.

In compounds of Formula (1)-(5), the promoiety —CH₂—C(R¹)₂—R³—R⁴ canhave any of the following structures, where R³ can be C₁₋₆ alkyl, suchas C₁₋₄ alkyl, such as methyl or ethyl:

In compounds of Formula (1)-(5), R² can be a single bond; R³ can be C₁₋₃alkyl; and each R¹ together with the carbon atom to which they arebonded can form a C₄₋₆ heterocycloalkyl ring or a substituted C₄₋₆heterocycloalkyl ring.

In compounds of Formula (1)-(5), R² can be a single bond; R³ can be C₁₋₃alkyl; and each R¹ together with the carbon atom to which they arebonded can form a C₄₋₆ heterocycloalkyl ring comprising two adjacent Satoms or a substituted C₄₋₆ heterocycloalkyl ring comprising at leastone heteroatom selected from O and S, and a carbonyl (═O) substituentgroup bonded to a carbon atom adjacent the heteroatom.

In compounds of Formula (1)-(5), R² can be a single bond; R³ can be C₁₋₃alkyl; and each R¹ together with the carbon atom to which they arebonded can form a 1,2-dithiolane, 1,2-dithane ring, thietan-2-one ring,dihydrothiophen-2(3H)-one ring, tetrahydro-2H-thipyran-2-one ring,oxetan-2-one ring dihydrofuran-2(3H)-one ring, ortetrahydro-2H-pyran-2-one ring.

In compounds of Formula (1)-(5),

each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be selected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴,—S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴), where R⁴ can be selected fromhydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and2-pyrrolidinyl.

In compounds of Formula (1)-(5),

each R¹ and the geminal carbon to which they are bonded can form a C₃₋₆cycloalkyl ring;

R² can be selected from a bond, methanediyl, ethanediyl, —CH(—OH)—,—CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be selected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴,—S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴), where R⁴ can be selected fromhydrogen, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, benzyl, and2-pyrrolidinyl.

In compounds of Formula (1)-(5),

R² can be a bond;

R³ be C₁₋₃ alkyl; and

each R¹ together with the carbon atom to which they are bonded can forma 1,2-dithiolante, 1,2-dithane ring, thietan-2-one ring,dihydrothiophen-2(3H)-one ring, tetrahydro-2H-thipyran-2-one ring,oxetan-2-one ring dihydrofuran-2(3H)-one ring, ortetrahydro-2H-pyran-2-one ring.

In compounds of Formula (1)-(5), each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be selected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴,—S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴);

wherein R⁴ can be selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉arylalkyl, and C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(5),

each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be —C(O)—O—R⁴;

wherein R⁴ can be selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉arylalkyl, and C₅₋₇ heterocycloalkyl.

In compounds of Formula (1)-(5),

each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and

R³ can be selected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴,—S—S—R⁴, —NHR⁴, and —CH(—NH₂)(—R⁴);

wherein R⁴ can be selected from methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene,oxetane-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.

In compounds of Formula (1)-(5),

each R¹ can be methyl;

R² can be selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ can be—C(O)—O—R⁴;

wherein R⁴ can be selected from methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene,oxetane-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.

In compounds of Formula (1)-(5),

each R¹ can be methyl;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴;

wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₇₋₁₀alkylarene, and C₅₋₁₀ heteroalkylcycloalkyl.

In compounds of Formula (1)-(5),

each R¹ can be methyl;

R² can be a single bond;

R³ can be —C(O)—O—R⁴;

wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₇₋₁₀alkylarene, and C₅₋₁₀ heteroalkylcycloalkyl;

each of R⁵, R⁶, and R⁷ can be hydrogen; and

A is a single bond.

In compounds of Formula (1)-(5), A can be a single bond, and each of R⁵,R⁶, and R⁷ can be hydrogen.

In compounds of Formula (1)-(5), A can be a single bond; each R¹ can beindependently C₁₋₃ alkyl; each R² can be a single bond; and each of R⁵,R⁶, and R⁷ can be hydrogen;

In compounds of Formula (1), the compound can be selected from:

-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    benzoate (2);-   ethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (3);-   benzyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (4);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    benzoate (6);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    propionate (7);-   benzyl    (4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl)    adipate (8);-   6-(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutoxy)-6-oxohexanoic    acid (9);-   methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (10);-   isopropyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (11);-   hexyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (12);-   heptyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (13);-   tert-butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (14);-   2-methoxyethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (15);-   oxetan-3-yl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (16);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate    (17);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate    (18);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate    (19);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    1H-imidazole-1-sulfonate (34);-   ethyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (35);-   hexyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (36);-   heptyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (37);-   2-methoxyethyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (38);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl    propionate (39);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl    benzoate (40);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl    2,6-dimethylbenzoate (41);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    pivalate (43);-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    3-chloro-2,6-dimethoxybenzoate (44);-   4-(((((1R,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl    2,6-dimethylbenzoate (45);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl    benzoate (46);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl    propionate (47);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    ((3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methyl) sulfate (48);-   2-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)phenyl    acetate (49);-   2-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)phenyl    pivalate (50);-   S-(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl)    ethanethioate (51);-   S-(5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl)    ethanethioate (52);-   S-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)    ethanethioate (53);-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    2,6-dimethylbenzoate (54);-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    adamantane-1-carboxylate (55);-   diethyl    2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate    (56);-   propyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (57);-   butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (58);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (59);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    pivalate (60);-   ethyl    2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate    (61);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    2,6-dimethylbenzoate (62);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    adamantane-1-carboxylate (63);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    2,6-dimethoxybenzoate (64);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl    benzoate (65);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl    2,6-dimethoxybenzoate (66);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl    2,6-dimethylbenzoate (67);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl    2-methylbenzoate (68);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl    3-chloro-2,6-dimethoxybenzoate (69);-   2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl    dibenzoate (70);-   2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl    diacetate (71);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl    2,6-dimethoxybenzoate (72);-   ethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylbutanoate    (73);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    ((3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (74);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

In compounds of Formula (1), the compound can be selected from:

-   ethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (3);-   benzyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (4);-   methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (10);-   isopropyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (11);-   hexyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (12);-   heptyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (13);-   tert-butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (14);-   2-methoxyethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (15);-   oxetan-3-yl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (16);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate    (17);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate    (18);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate    (19);-   hexyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (36);-   heptyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (37);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);-   S-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)    ethanethioate (53);-   propyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (57);-   butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (58);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (59);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

In compounds of Formula (1), the compound can be selected from:

-   ethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (3);-   benzyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (4);-   methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (10);-   isopropyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (11);-   hexyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (12);-   heptyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (13);-   tert-butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (14);-   2-methoxyethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (15);-   oxetan-3-yl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (16);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate    (17);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate    (18);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate    (19);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

In compounds of Formula (1), the compound can be selected from:

-   hexyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (36);-   heptyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (37);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);-   S-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)    ethanethioate (53);-   propyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (57);-   butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (58);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (59);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

In a compound of Formula (2a),

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the geminal carbon atom to which they are bonded form aC₃₋₆ cycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring, a C₃₋₆heterocycloalkyl ring, or a substituted C₃₋₆ heterocycloalkyl ring;

R² can be a single bond;

R³ can be —C(O)—O—R⁴; and

R⁴ can be selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl,C₅₋₇ heterocycloalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈heteroalkyl, substituted C₇₋₉ arylalkyl, and substituted C₅₋₇heterocycloalkyl.

In a compound of Formula (2a),

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be selected from single bond, methane-diyl, and ethane-diyl; and

R³ can be selected from —C(O)—O—R⁴ and —S—C(O)—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆heterocycloalkyl, and substituted C₄₋₁₀ heterocycloalkylalkyl.

In a compound of Formula (2a),

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴, where R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

In a compound of Formula (2a),

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be —(CH₂)₂—; and

R³ can be —C(O)—O—R⁴ wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

In a compound of Formula (2a),

each R¹ can be selected from C₁₋₃ alkyl, or each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring;

R² can be —CH₂—; and

R³ can be —S—C(O)—R⁴, wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, substituted C₄₋₁₀heterocycloalkylalkyl.

In a compound of Formula (2a),

each R¹ together with the carbon atom to which they are bonded form aC₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a C₃₋₆ cycloalkylring, or a C₃₋₆ heterocycloalkyl ring;

R² can be a single bond; and

R³ can be C₁₋₃ alkyl.

In a compound of Formula (2a),

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from a single bond and methanediyl; and

R³ can be selected from —O—C(O)—R⁴ and —C(O)—O—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl and substituted phenyl.

In a compound of Formula (2a),

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be a single bond;

R³ can be —CH═C(R⁴)₂, wherein each R⁴ can be —C(O)—O—R⁸, or each R⁴together with the carbon atom to which they are bonded from asubstituted heterocyclohexyl ring; and

each R⁸ can be C₁₋₄ alkyl.

In a compound of Formula (2a),

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from a single bond and methanediyl; and

R³ can be substituted phenyl, wherein the one or more substituents canbe independently selected from —CH₂—O—C(O)—R⁴ and —O—C(O)—R⁴, wherein R⁴can be selected from C₁₋₁₀ alkyl and phenyl.

In a compound of Formula (2a),

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from —C(R⁸)₂— and —CH₂—C(R⁸)₂—, wherein each R⁸ canbe independently selected from C₁₋₃ alkyl; and

R³ can be selected from —C(O)—O—R⁴ and —O—C(O)—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, substituted C₁₋₁₀ alkyl,substituted C₁₋₁₀ heteroalkyl, and4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

In a compound of Formula (2a),

each R¹ together with the carbon atom to which they are bonded form asubstituted C₅₋₆ heterocyclic ring;

R² can be a single bond; and

R³ can be C₁₋₃ alkyl.

A compound of Formula (1) can be a compound of sub-genus (1A), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be selected from single bond, methane-diyl, and ethane-diyl; and

R³ can be selected from —C(O)—O—R⁴ and —S—C(O)—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆heterocycloalkyl, and substituted C₄₋₁₀ heterocycloalkylalkyl.

In compounds of subgenus (1A), each R¹ can be independently selectedfrom C₁₋₃ alkyl.

In compounds of subgenus (1A), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring.

In compounds of subgenus (1A), R² a single bond.

In compounds of subgenus (1A), R² can be methane-diyl.

In compounds of subgenus (1A), R² can be ethane-diyl.

In compounds of subgenus (1A), R³ can be —C(O)—O—R⁴.

In compounds of subgenus (1A), R³ can be —S—C(O)—R⁴.

In compounds of subgenus (1A), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1A), R⁴ can be C₁₋₁₀ heteroalkyl.

In compounds of subgenus (1A), R⁴ can be C₅₋₁₀ arylalkyl.

In compounds of subgenus (1A), R⁴ can be C₃₋₆ heterocycloalkyl.

In compounds of subgenus (1A), R⁴ can be substituted C₄₋₁₀heterocycloalkylalkyl.

A compound of Formula (1) can be a compound of sub-genus (1B), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴, where R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

In compounds of subgenus (1B), each R¹ can be independently selectedfrom C₁₋₃ alkyl.

In compounds of subgenus (1B), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring.

In compounds of subgenus (1B), R⁴ can be selected from C₁₋₇ alkyl, C₁₋₁₀heteroalkyl wherein the one or more heteroatoms can be oxygen, —CH₂—C₄₋₆cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl wherein theone or more heteroatoms can be oxygen, and —CH₂—C₃₋₆ substitutedheterocycloalkyl, and —(CH₂)₂—C₃₋₆ substituted heterocycloalkyl.

In compounds of subgenus (1B), in the substituted C₃₋₆ heterocycloalkylthe one or more heteroatoms can be oxygen, and the one or moresubstituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1B), each R¹ can be methyl, or each R¹together with the carbon atom to which they are bonded form a cyclohexylring or a cyclopentyl ring.

In compounds of subgenus (1B), R⁴ can be selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, n-hexyl, n-heptyl, —CH₂—CH₂—O—CH₃,benzyl, 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

In compounds of subgenus (1B),

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be methyl, or each R¹ together with the carbon atom to whichthey are bonded form a cyclohexyl ring or a cyclopentyl ring;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴, wherein R⁴ can be selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, n-hexyl, n-heptyl, —CH₂—CH₂—O—CH₃,—CH₂-phenyl (benzyl), 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

A compound of Formula (1) can be a compound of sub-genus (1C), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be —(CH₂)₂—; and

R³ can be —C(O)—O—R⁴ wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

In compounds of subgenus (1C), each R¹ can be independently selectedfrom C₁₋₃ alkyl.

In compounds of subgenus (1C), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring.

In compounds of subgenus (1C), R⁴ can be selected from C₁₋₇ alkyl, C₁₋₁₀heteroalkyl wherein the one or more heteroatoms can be oxygen, —CH₂—C₄₋₆cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl wherein theone or more heteroatoms can be oxygen, —CH₂—C₃₋₆ substitutedheterocycloalkyl, and —(CH₂)₂—C₃₋₆ substituted heterocycloalkyl.

In compounds of subgenus (1C), in the substituted C₃₋₆ heterocycloalkylthe one or more heteroatoms can be oxygen, and the one or moresubstituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1C), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1C),

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be methyl;

R² can be —(CH₂)₂—; and

R³ can be —C(O)—O—R⁴ wherein R⁴ can be selected from n-hexyl andn-heptyl.

A compound of Formula (1) can be a compound of sub-genus (1D), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be selected from C₁₋₃ alkyl, or each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring;

R² can be —CH₂—; and

R³ can be —S—C(O)—R⁴, wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, substituted C₄₋₁₀heterocycloalkylalkyl.

In compounds of subgenus (1D), each R¹ can be independently selectedfrom C₁₋₃ alkyl.

In compounds of subgenus (1D), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring.

In compounds of subgenus (1D), R⁴ can be selected from C₁₋₇ alkyl, C₁₋₁₀heteroalkyl wherein the one or more heteroatoms can be oxygen, —CH₂—C₄₋₆cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl wherein theone or more heteroatoms can be oxygen, —CH₂—C₃₋₆ substitutedheterocycloalkyl, —(CH₂)₂—C₃₋₆ substituted heterocycloalkyl.

In compounds of subgenus (1D), in the substituted C₃₋₆ heterocycloalkylthe one or more heteroatoms can be oxygen, and the one or moresubstituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1D), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1D),

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be methyl;

R² can be —CH₂—; and

R³ can be —S—C(O)—R⁴, wherein R⁴ can be methyl.

A compound of Formula (1) can be a compound of sub-genus (1E), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ together with the carbon atom to which they are bonded form aC₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a C₃₋₆ cycloalkylring, or a C₃₋₆ heterocycloalkyl ring;

R² can be a single bond; and

R³ can be C₁₋₃ alkyl.

In compounds of subgenus (1E), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ heterocycloalkyl ring or a C₃₋₆heterocycloalkyl ring;

In compounds of subgenus (1E), the one or more heteroatoms can be oxygenand the one or more substituents can be ═O.

In compounds of subgenus (1E),

each R¹ together with the carbon atom to which they are bonded form adihydrofuran-2(3H)-one ring;

R² can be a single bond; and

R³ can be methyl.

A compound of Formula (1) can be a compound of sub-genus (1F), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from a single bond and methanediyl; and

R³ can be selected from —O—C(O)—R⁴ and —C(O)—O—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl and substituted phenyl.

In compounds of subgenus (1F), R² can be a single bond.

In compounds of subgenus (1F), R² can be methanediyl.

In compounds of subgenus (1F), R³ can be —O—C(O)—R⁴.

In compounds of subgenus (1F), R² can be methanediyl; and R³ can be—O—C(O)—R⁴.

In compounds of subgenus (1F), R³ can be —C(O)—O—R⁴.

In compounds of subgenus (1F), R² can be a single bond; and R³ can be—C(O)—O—R⁴.

In compounds of subgenus (1E), R² can be a single bond; R³ can be—C(O)—O—R⁴; and R⁴ can be C₁₋₃ alkyl.

In compounds of subgenus (1F), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1F), R⁴ can be C₁₋₄ alkyl.

In compounds of subgenus (1F), R⁴ can be substituted phenyl.

In compounds of subgenus (1F), R² can be methanediyl; R³ can be—O—C(O)—R⁴; and R⁴ can be substituted phenyl.

In compounds of subgenus (1F), the one or more substituents can beindependently selected from halogen, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In compounds of subgenus (1F), the substituted phenyl can be2,6-substituted phenyl.

In compounds of subgenus (1F), each of the substituents can be selectedfrom C₁₋₃ alkyl and C₁₋₃ alkoxy.

In compounds of subgenus (1F), the substituted phenyl can be2,5,6-substituted phenyl.

In compounds of subgenus (1F), each of the substituents at the 2 and 6positions can be independently selected from C₁₋₃ alkyl and C₁₋₃ alkoxy;and the substituent at the 5 position can be halogen.

A compound of Formula (1) can be a compound of sub-genus (1G), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be a single bond; and

R³ can be —CH═C(R⁴)₂, wherein each R⁴ can be —C(O)—O—R⁸, or each R⁴together with the carbon atom to which they are bonded from asubstituted heterocyclohexyl ring; and

each R⁸ can be C₁₋₄ alkyl.

In compounds of subgenus (1G), each R⁴ can be —C(O)—O—R⁸.

In compounds of subgenus (1G), each R⁴ can be —C(O)—O—R⁸, or each R⁴together with the carbon atom to which they are bonded from asubstituted heterocyclohexyl ring.

In compounds of subgenus (1G), in the substituted heterocyclohexyl ring,the one or more heteroatoms can be oxygen.

In compounds of subgenus (1G), in the substituted heterocyclohexyl ring,the one or more substituents can be independently selected from C₁₋₃alkyl and ═O.

In compounds of subgenus (1G), the substituted heterocycloalkyl ring canbe 2,2-dimethyl-5-yl-1,3-dioxane-4,6-dione.

A compound of Formula (1) can be a compound of sub-genus (1H), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from a single bond and methanediyl; and

R³ can be substituted phenyl, wherein the one or more substituents canbe independently selected from —CH₂—O—C(O)—R⁴ and —O—C(O)—R⁴, wherein R⁴can be selected from C₁₋₁₀ alkyl and phenyl.

In compounds of subgenus (1H), R² can be a single bond.

In compounds of subgenus (1H), R² can be 2-substituted phenyl.

In compounds of subgenus (1H), the one or more substituents can be—CH₂—O—C(O)—R⁴.

In compounds of subgenus (1H), the one or more substituents can be—O—C(O)—R⁴.

In compounds of subgenus (1H), R⁴ can be C₁₋₁₀ alkyl.

In compounds of subgenus (1H), R⁴ can be selected from methyl, ethyl,iso-propyl, pivalolyl, and phenyl.

A compound of Formula (1) can be a compound of sub-genus (11), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from —C(R⁸)₂— and —CH₂—C(R⁸)₂—, wherein each R⁸ canbe independently selected from C₁₋₃ alkyl; and

R³ can be selected from —C(O)—O—R⁴ and —O—C(O)—R⁴, wherein R⁴ can beselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, substituted C₁₋₁₀ alkyl,substituted C₁₋₁₀ heteroalkyl, and4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

In compounds of subgenus (11), each R¹ can be methyl.

In compounds of subgenus (11), R² can be —C(R⁸)₂—.

In compounds of subgenus (11), R² can be —CH₂—C(R⁸)₂—.

In compounds of subgenus (11), each R⁸ can be methyl.

In compounds of subgenus (11), each R¹ can be methyl; and each R⁸ can bemethyl.

In compounds of subgenus (11), R³ can be —C(O)—O—R⁴.

In compounds of subgenus (11), R³ can be —O—C(O)—R⁴.

A compound of Formula (1) can be a compound of sub-genus (1J), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ together with the carbon atom to which they are bonded form asubstituted C₅₋₆ heterocyclic ring;

R² can be a single bond; and

R³ can be C₁₋₃ alkyl.

In compounds of subgenus (1J), in the substituted C₅₋₆ heterocyclicring, the one or more heteroatoms can be oxygen; and the one or moresubstituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1J), each R¹ together with the carbon atom towhich they are bonded form a tetrahydro-2H-pyran-2-one ring.

In compounds of subgenus (1J),

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be independently selected from C₁₋₃ alkyl;

R² can be selected from C₂₄ alkanediyl; and

R³ can be substituted C₅₋₆ heterocycloalkyl, wherein the one or moreheteroatoms can be independently selected from N and O; and the one ormore substituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of subgenus (1J), R³ can have the structure of Formula (6):

wherein R⁹ can be selected from hydrogen, C₁₋₆ alkyl, C₄₋₆ cycloalkyl,C₁₋₆ heteroalkyl, C₄₋₆ heterocycloalkyl, substituted C₁₋₆ alkyl,substituted C₄₋₆ cycloalkyl, substituted C₁₋₆ heteroalkyl, andsubstituted C₄₋₆ heterocycloalkyl.

In compounds of subgenus (1J), R⁹ can be selected from hydrogen and C₁₋₆alkyl such as C₁₋₄ alkyl such as methyl or ethyl.

A compound of Formula (4) can be a compound of sub-genus (4A), or apharmaceutically acceptable salt thereof, wherein,

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

each R¹ can be independently selected from C₁₋₃ alkyl, or each R¹together with the carbon atom to which they are bonded form a C₃₋₆cycloalkyl ring;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴, wherein R⁴ can be selected from C₁₋₁₀ alkyl, C₁₋₁₀heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and substitutedC₄₋₁₀ heterocycloalkylalkyl.

In compounds of sub-genus (4A), each R¹ can be independently selectedfrom C₁₋₃ alkyl.

In compounds of sub-genus (4A), each R¹ together with the carbon atom towhich they are bonded form a C₃₋₆ cycloalkyl ring.

In compounds of sub-genus (4A), R⁴ can be selected from C₁₋₇ alkyl,C₁₋₁₀ heteroalkyl wherein the one or more heteroatoms can be oxygen,—CH₂—C₄₋₆ cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl, C₃₋₆ heterocycloalkylwherein the one or more heteroatoms can be oxygen, —CH₂—C₃₋₆ substitutedheterocycloalkyl, and —(CH₂)₂—C₃₋₆ substituted heterocycloalkyl.

In compounds of sub-genus (4A), in the substituted C₃₋₆ heterocycloalkylthe one or more heteroatoms can be oxygen, and the one or moresubstituents can be independently selected from C₁₋₃ alkyl and ═O.

In compounds of sub-genus (4A), each R¹ can be methyl, or each R¹together with the carbon atom to which they are bonded form a cyclohexylring or a cyclopentyl ring.

In compounds of sub-genus (4A), R⁴ can be selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, n-hexyl, n-heptyl, —CH₂—CH₂—O—CH₃,benzyl, 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

In compounds of sub-genus (4A),

each of R⁵, R⁶, and R⁷ can be hydrogen;

A can be a single bond;

R² can be a single bond; and

R³ can be —C(O)—O—R⁴, wherein R⁴ can be C₁₋₁₀ alkyl.

A compound of Formula (4) can be selected from:

-   ethyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (20);-   2-methoxyethyl    2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (21);-   4-((1R,2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (22);-   4-((1R,2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (23);-   4-((1R,2S,5R)-6-((((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (24);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (25);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

A compound of Formula (4) can be selected from:

-   ethyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (20);-   4-((1R,2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (22);-   4-((1R,2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (23);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (25);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

A compound of Formula (5) can be selected from:

-   ethyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (27);-   2-methoxyethyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (28);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    TFA salt (29);-   hexyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    TFA salt (30);-   heptyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    TFA salt (31);-   ethyl    1-((((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate    TFA salt (32);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

A compound of Formula (1)-(5) can be a solvate, a pharmaceuticallyacceptable salt, or a combination thereof.

In compounds of Formula (1)-(5), a pharmaceutically acceptable salt canbe the hydrochloride salt.

In compounds of Formula (1)-(5), a pharmaceutically acceptable salt canbe the dihydrochloride salt.

A compound of Formula (1)-(5) can be a pharmaceutically acceptable saltof a compound of Formula (1)-(5), a hydrate thereof, or a solvate of anyof the foregoing.

The compound described herein may be synthesized using methods known inthe art. The synthesis of the various diazabicyclo[3.2.1]octanestructures described herein are conventional and are well known to thoseof skill in the art (Tandiparthi et al., PCT International ApplicationPublication No. WO 2016/116788; Lampilas et al., U.S. Pat. No.7,112,592; King et al., ACS Chemical Biology 2016; 11, 864; and Bush etal., Cold Spring Harb Perspect Med 2016; 6:a025247). Formation ofsulfate esters is also well-known in the art (Simpson et al., J. Am.Chem. Soc. 2006, 128, 1605; Li et al., U.S. Application Publication No.2009/0099253; Jandeleit et al., PCT International ApplicationPublication No. WO 2009/033054; Jandeleit et al., PCT InternationalApplication Publication No. WO 2009/033079; and Jandeleit et al., PCTInternational Application Publication No. WO 2011/150380).

Sulfate monoester analogs of sulfate-containing compounds can beprepared by reacting a hydroxyl-substituted sulfate-containing compoundwith a chlorosulfate monoester to provide the corresponding sulfatemonoester analog. The methods can be useful in preparing prodrugs ofsulfate-containing pharmaceutical compounds.

Prodrugs are derivatized forms of drugs that following administrationare converted or metabolized to an active form of the parent drug invivo. Prodrugs are used to modify one or more aspects of thepharmacokinetics of a drug in a manner that enhances the therapeuticefficacy of a parent drug. For example, prodrugs are often used toenhance the oral bioavailability of a drug. To be therapeuticallyeffective, drugs exhibiting poor oral bioavailability may requirefrequent dosing, large administered doses, or may need to beadministered by other than oral routes, such as intravenously. Inparticular, many drugs with sulfate groups exhibit poor oralbioavailability.

Intramolecular cyclization prodrug strategies have been used to modifythe pharmacokinetics of drugs. Intramolecular cyclization releaseprodrug strategies have been applied to drugs containing sulfonic acidfunctional groups. For example, prodrugs comprising a substitutedneopentyl sulfonate ester derivative in which the neopentyl group isremoved in vivo by unmasking a nucleophilic heteroatom bonded to asubstituted neopentyl moiety followed by intramolecular cyclization togenerate the parent drug in the sulfonic acid or sulfonic salt form havebeen described, for example, in U.S. Pat. Nos. 7,994,218 and 8,168,617.In such prodrugs the nucleophilic heteroatom can be nitrogen or oxygenand the nitrogen or oxygen nucleophile can be masked with an amine oralcohol protecting group, respectively, capable of being deprotected invivo.

Sulfate monoester analogs of a sulfate-containing compound can beprepared by reacting a hydroxyl-substituted analog of thesulfate-containing compound with a chlorosulfate monoester under basicconditions, to provide the corresponding sulfate monoester analog. Achlorosulfate monoester can be prepared by reacting sulfuryl chloridewith an alcohol having the desired promoiety. Neopentyl alcohols havingneopentyl promoieties can be prepared by standard synthetic methods suchas those described in U.S. Pat. Nos. 7,994,218 and 8,168,617.

For example, sulfate monoester analogs of avibactam provided by thepresent disclosure can be synthesized by reacting(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamidewith a chlorosulfate monoester having a desired promoiety to provide thecorresponding(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfatemonoester.

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamidecan be prepared by hydrogenating(1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamideusing the methods described, for example, in U.S. Pat. Nos. 8,772,490;9,035,062; and 9,284,273.

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamidecan be reacted with the chlorosulfate monoester in the presence of abase to provide the corresponding sulfate monoester analog of avibactam.Suitable methods are disclosed, for example, in J. Am. Chem. Soc. 2006,128, 1605-1610.

Similar methods can be adapted to prepare sulfate monoester analogs ofrelebactam and nacubactam. For example, the tert-butyl carboxylateprotected, 6-hydroxyl analog of relebactam can be reacted with achlorosulfate monoester in the presence of a base to provide thecorresponding tert-butyl carboxylate protected sulfate monoester analogof relebactam. The compound can then be deprotected in the presence ofan acid to provide the sulfate monoester analog of relebactam. Methodssimilar to those used to prepare sulfate monoester analogs of relebactamcan be used to prepare sulfate monoester analogs of nacubactam.

For example, a sulfate monoester analog of a sulfate monoester ofFormula (80a) can be synthesized by reacting a cyclic hydroxamic acid ofFormula (80b) with a chlorosulfonate monoester of Formula (80c) underbasic conditions:

where,

R is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈ cycloalkyl, C₅₋₈heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀ heterocycloalkylalkyl,C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀ arylalkyl, C₅₋₁₀ heteroarylalkyl,substituted C₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl, substituted C₅₋₈cycloalkyl, substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl, substitutedC₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted C₇₋₁₀ arylalkyl, andsubstituted C₅₋₁₀ heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

A is a single bond (—) and R⁷ is hydrogen, or A is a double bond (═) andR⁷ is C₁₋₃ alkyl.

The chlorosulfate monoester can comprise a chlorosulfate neopentylester, such as a chlorosulfate neopentyl ester of Formula (81):

wherein,

-   -   each R¹ is independently selected from C₁₋₆ alkyl, or each R¹        and the geminal carbon atom to which they are bonded forms a        C₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a        substituted C₃₋₆ cycloalkyl ring, or a substituted C₃₋₆        heterocycloalkyl ring;    -   R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆        heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆        heterocycloalkanediyl, C₆ arenediyl, C₅₋₆ heteroarenediyl,        substituted C₁₋₆ alkanediyl, substituted C₁₋₆ heteroalkanediyl,        substituted C₅₋₆ cycloalkanediyl, substituted C₅₋₆        heterocycloalkanediyl, substituted C₆ arenediyl, and substituted        C₅₋₆ heteroarenediyl; and    -   R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴,        —NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴,        —C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴,        —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆        heterocycloalkyl, C₅₋₆ heteroaryl, substituted C₅₋₆ cycloalkyl,        substituted C₅₋₆ heterocycloalkyl, substituted C₅₋₆ aryl,        substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂, wherein,    -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl.

The chlorosulfate monoester can be synthesized by reacting an alcoholsuch as a neopentyl alcohol with sulfuryl chloride.

The method can be used to bond any suitable chlorosulfonate ester to acyclic hydroxamic acid such as, for example, a chlorosulfonate ester ofFormula (82) and a cyclic hydroxamic acid of Formula (83) to provide thecorresponding sulfate monoester analog of Formula (84):

where,

R can be selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈ cycloalkyl,C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀ arylalkyl,C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈heteroalkyl, substituted C₅₋₈ cycloalkyl, substituted C₅₋₈heterocycloalkyl, substituted C₅₋₁₀ cycloalkylalkyl, substituted C₅₋₁₀heterocycloalkylalkyl, substituted C₆₋₈ aryl, substituted C₅₋₈heteroaryl, substituted C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀heteroarylalkyl;

n can be an integer from 1 to 6;

each A can be independently selected from —(CH₂)—, —(CHR)—, —(CR₂)—,—NH—, —NR—, O, and S, where R is independently elected from hydrogen,C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl,C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈heteroaryl, C₇₋₁₀ arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈alkyl, substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀ cycloalkylalkyl,substituted C₅₋₁₀ heterocycloalkylalkyl, substituted C₆₋₈ aryl,substituted C₅₋₈ heteroaryl, substituted C₇₋₁₀ arylalkyl, andsubstituted C₅₋₁₀ heteroarylalkyl; or one A is bonded to another Athrough a group -L-, where L is selected from C₁₋₈ alkyl, C₁₋₈heteroalkyl, substituted C₁₋₈ alkyl, and substituted C₁₋₈ heteroalkyl.

R can further include any of the promoieties disclosed herein, such as apromoiety having the structure:

where R¹, R², and R³ are defined as in Formula (1).

The compositions provided herein contain therapeutically effectiveamounts of one or more of the compounds provided herein that are usefulin the prevention, treatment, or amelioration of one or more of thesymptoms of diseases or disorders described herein and a vehicle.Vehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration. In addition, thecompounds may be formulated as the sole active ingredient in thecomposition or may be combined with other active ingredients.

The compositions contain one or more compounds provided herein. Thecompounds are, in some embodiments, formulated into suitablepreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor parenteral administration, as well as topical administration,transdermal administration and oral inhalation via nebulizers,pressurized metered dose inhalers and dry powder inhalers. In someembodiments, the compounds described above are formulated intocompositions using techniques and procedures well known in the art (see,e.g., Ansel, Introduction to Pharmaceutical Dosage Forms, SeventhEdition (1999)).

In the compositions, effective concentrations of one or more compoundsor derivatives thereof is (are) mixed with a suitable vehicle. Thecompounds may be derivatized as the corresponding salts, esters, enolethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals,acids, bases, solvates, ion-pairs, hydrates or prodrugs prior toformulation, as described above. The concentrations of the compounds inthe compositions are effective for delivery of an amount, uponadministration that treats, leads to prevention, or amelioration of oneor more of the symptoms of diseases or disorders described herein. Insome embodiments, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction of acompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved, prevented, or one or more symptoms areameliorated.

The active compound is included in the vehicle in an amount sufficientto exert a therapeutically useful effect in the absence of undesirableside effects on the patient treated. The therapeutically effectiveconcentration may be predicted empirically by testing the compounds inin vitro and in vivo systems well known to those of skill in the art andthen extrapolated therefrom for dosages for humans. Human doses are thentypically fine-tuned in clinical trials and titrated to response.

The concentration of active compound in the composition will depend onabsorption, inactivation and excretion rates of the active compound, thephysicochemical characteristics of the compound, the dosage schedule,and amount administered as well as other factors known to those of skillin the art. For example, the amount that is delivered is sufficient toameliorate one or more of the symptoms of diseases or disorders asdescribed herein.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used such as use of liposomes,prodrugs, complexation/chelation, nanoparticles, or emulsions ortertiary templating. Such methods are known to those of skill in thisart, and include, but are not limited to, using co-solvents, such asdimethyl sulfoxide (DMSO), using surfactants or surface modifiers, suchas TWEEN®, complexing agents such as cyclodextrin or dissolution byenhanced ionization (i.e. dissolving in aqueous sodium bicarbonate).Derivatives of the compounds, such as prodrugs of the compounds may alsobe used in formulating effective compositions.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedvehicle. The effective concentration is sufficient for ameliorating thesymptoms of the disease, disorder or condition treated and may beempirically determined.

The compositions are provided for administration to humans and animalsin indication appropriate dosage forms, such as dry powder inhalers(DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets,capsules, pills, sublingual tapes/bioerodible strips, tablets orcapsules, powders, granules, lozenges, lotions, salves, suppositories,fast melts, transdermal patches or other transdermal applicationdevices/preparations, sterile parenteral solutions or suspensions, andoral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or derivatives thereof. Thetherapeutically active compounds and derivatives thereof are, in someembodiments, formulated and administered in unit-dosage forms ormultiple-dosage forms. Unit-dose forms as used herein refer tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit-dose contains apredetermined quantity of the therapeutically active compound sufficientto produce the desired therapeutic effect, in association with therequired vehicle. Examples of unit-dose forms include ampoules andsyringes and individually packaged tablets or capsules. Unit-dose formsmay be administered in fractions or multiples thereof. A multiple-doseform is a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dose form. Examples ofmultiple-dose forms include vials, bottles of tablets or capsules orbottles of pints or gallons. Hence, multiple dose form is a multiple ofunit-doses which are not segregated in packaging.

Liquid compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing an active compound as defined above andoptional adjuvants in a vehicle, such as, for example, water, saline,aqueous dextrose, glycerol, glycols, ethanol, and the like, to therebyform a solution or suspension, colloidal dispersion, emulsion orliposomal formulation. If desired, the composition to be administeredmay also contain minor amounts of nontoxic auxiliary substances such aswetting agents, emulsifying agents, solubilizing agents, pH bufferingagents and the like, for example, acetate, sodium citrate, cyclodextrinderivatives, sorbitan monolaurate, triethanolamine sodium acetate,triethanolamine oleate, and other such agents.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975 or later editions thereof.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from vehicle or carrier maybe prepared. Methods for preparation of these compositions are known tothose skilled in the art. The contemplated compositions may contain0.001%-100% active ingredient, in one embodiment 0.1-95%, in anotherembodiment 0.4-10%.

Compositions can be lactose-free compositions containing excipients thatare well known in the art and are listed, for example, in the U.S.Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositionscontain active ingredients, a binder/filler, and a lubricant incompatible amounts. Particular lactose-free dosage forms contain activeingredients, microcrystalline cellulose, pre-gelatinized starch, andmagnesium stearate.

Further provided are anhydrous compositions and dosage forms comprisingactive ingredients, since water can facilitate the degradation of somecompounds. For example, the addition of water (e.g., 5%) is widelyaccepted as a means of simulating long-term storage in order todetermine characteristics such as shelf-life or the stability offormulations over time. See, e.g., Jens T. Carstensen, Drug Stability:Principles &Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80.In effect, water and heat accelerate the decomposition of somecompounds. Thus, the effect of water on a formulation can be of greatsignificance since moisture and/or humidity are commonly encounteredduring manufacture, handling, packaging, storage, shipment, and use offormulations.

Anhydrous compositions and dosage forms provided herein can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions.

An anhydrous composition should be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions aregenerally packaged using materials known to prevent exposure to watersuch that they can be included in suitable formulary kits. Examples ofsuitable packaging include, but are not limited to, hermetically sealedfoils, plastics, unit dose containers (e.g., vials), blister packs, andstrip packs.

Oral dosage forms are either solid, gel or liquid. The solid dosageforms are tablets, capsules, granules, and bulk powders. Types of oraltablets include compressed, chewable lozenges and tablets which may beenteric-coated, sugar-coated or film-coated. Capsules may be hard orsoft gelatin capsules, while granules and powders may be provided innon-effervescent or effervescent form with the combination of otheringredients known to those skilled in the art.

Formulations can be solid dosage forms such as for example, capsules ortablets. The tablets, pills, capsules, troches and the like can containone or more of the following ingredients, or compounds of a similarnature: a binder; a lubricant; a diluent; a glidant; a disintegratingagent; a coloring agent; a sweetening agent; a flavoring agent; awetting agent; an enteric coating; a film coating agent and modifiedrelease agent. Examples of binders include microcrystalline cellulose,methyl paraben, polyalkyleneoxides, gum tragacanth, glucose solution,acacia mucilage, gelatin solution, molasses, polyvinylpyrrolidine,povidone, crospovidones, sucrose and starch and starch derivatives.Lubricants include talc, starch, magnesium/calcium stearate, lycopodiumand stearic acid. Diluents include, for example, lactose, sucrose,trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol anddicalcium phosphate. Glidants include, but are not limited to, colloidalsilicon dioxide. Disintegrating agents include crosscarmellose sodium,sodium starch glycolate, alginic acid, corn starch, potato starch,bentonite, methylcellulose, agar and carboxymethylcellulose. Coloringagents include, for example, any of the approved certified water-solubleFD and C dyes, mixtures thereof; and water insoluble FD and C dyessuspended on alumina hydrate and advanced coloring or anti-forgerycolor/opalescent additives known to those skilled in the art. Sweeteningagents include sucrose, lactose, mannitol and artificial sweeteningagents such as saccharin and any number of spray dried flavors.Flavoring agents include natural flavors extracted from plants such asfruits and synthetic blends of compounds which produce a pleasantsensation or mask unpleasant taste, such as, but not limited topeppermint and methyl salicylate. Wetting agents include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether. Enteric-coatings include fatty acids,fats, waxes, shellac, ammoniated shellac and cellulose acetatephthalates. Film coatings include hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000 and cellulose acetatephthalate. Modified release agents include polymers such as theEudragit® series and cellulose esters.

The compound, or derivative thereof, can be provided in a compositionthat protects it from the acidic environment of the stomach. Forexample, the composition can be formulated in an enteric coating thatmaintains its integrity in the stomach and releases the active compoundin the intestine. The composition may also be formulated in combinationwith an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H₂ blockers, and diuretics. The activeingredient is a compound or derivative thereof as described herein.Higher concentrations, up to about 98% by weight of the activeingredient may be included.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations. Vehicles usedin elixirs include solvents. Syrups are concentrated aqueous solutionsof a sugar, for example, sucrose, and may contain a preservative. Anemulsion is a two-phase system in which one liquid is dispersed in theform of small globules throughout another liquid. Carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use suspending agents and preservatives. Acceptablesubstances used in non-effervescent granules, to be reconstituted into aliquid oral dosage form, include diluents, sweeteners and wettingagents. Acceptable substances used in effervescent granules, to bereconstituted into a liquid oral dosage form, include organic acids anda source of carbon dioxide. Coloring and flavoring agents are used inall of the above dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicacid, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Sweetening agents include sucrose, syrups, glycerin andartificial sweetening agents such as saccharin. Wetting agents includepropylene glycol monostearate, sorbitan monooleate, diethylene glycolmonolaurate and polyoxyethylene lauryl ether. Organic acids includecitric and tartaric acid. Sources of carbon dioxide include sodiumbicarbonate and sodium carbonate. Coloring agents include any of theapproved certified water-soluble FD and C dyes, and mixtures thereof.Flavoring agents include natural flavors extracted from plants suchfruits, and synthetic blends of compounds which produce a pleasant tastesensation.

For a solid dosage form, the solution or suspension, in for example,propylene carbonate, vegetable oils or triglycerides, is in someembodiments encapsulated in a gelatin capsule. Such solutions, and thepreparation and encapsulation thereof, are disclosed in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, thesolution, e.g., for example, in a polyethylene glycol, may be dilutedwith a sufficient quantity of a liquid vehicle, e.g., water, to beeasily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. RE28,819 and4,358,603. Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpolyalkylene glycol, including, but not limited to, 1,2-dimethoxyethane,diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether,polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethylether wherein 350, 550 and 750 refer to the approximate averagemolecular weight of the polyethylene glycol, and one or moreantioxidants, such as butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including an acetal. Alcohols used in these formulations areany water-miscible solvents having one or more hydroxyl groups,including, but not limited to, propylene glycol and ethanol. Acetalsinclude, but are not limited to, di(lower alkyl) acetals of lower alkylaldehydes such as acetaldehyde diethyl acetal.

Parenteral administration, in some embodiments characterized byinjection, either subcutaneously, intramuscularly or intravenously isalso contemplated herein. Injectables can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution or suspension in liquid prior to injection, or asemulsions. The injectables, solutions and emulsions also contain one ormore excipients. Suitable excipients are, for example, water, saline,dextrose, glycerol or ethanol. In addition, if desired, the compositionsto be administered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins.

Implantation of a slow-release or sustained-release system, such that aconstant level of dosage is maintained (see, e.g., U.S. Pat. No.3,710,795) is also contemplated herein. Briefly, a compound providedherein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Vehicles used in parenteral preparations include aqueous vehicles,nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers,antioxidants, local anesthetics, suspending and dispersing agents,emulsifying agents, sequestering or chelating agents and othersubstances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcellulose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (Tween® 80). A sequestering or chelatingagent of metal ions includes EDTA. Carriers also include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles;and sodium hydroxide, hydrochloric acid, citric acid or lactic acid forpH adjustment.

The concentration of compound is adjusted so that an injection providesan effective amount to produce the desired pharmacological effect. Theexact dose depends on the age, weight, body surface area and conditionof the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration. In someembodiments, a therapeutically effective dosage is formulated to containa concentration of at least 0.01% w/w up to 90% w/w or more, such asmore than 0.1% w/w of the active compound to the treated tissue(s).

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108;5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830;6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981;6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634.Such dosage forms can be used to provide slow or controlled-release ofone or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, liposomes, microspheres,or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled-release formulations known tothose of ordinary skill in the art, including those described herein,can be readily selected for use with the active ingredients providedherein.

All controlled-release products have a common goal of improving drugtherapy over that achieved by their non-controlled counterparts.Ideally, the use of an optimally designed controlled-release preparationin medical treatment is characterized by a minimum of drug substancebeing employed to cure or control the condition in a minimum amount oftime. Advantages of controlled-release formulations include extendedactivity of the drug, reduced dosage frequency, and increased patientcompliance. In addition, controlled-release formulations can be used toaffect the time of onset of action or other characteristics, such asblood levels of the drug, and can thus affect the occurrence of side(e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

An agent may be administered using intravenous infusion, an implantableosmotic pump, a transdermal patch, liposomes, or other modes ofadministration. In some embodiments, a pump may be used (see, Sefton,CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In otherembodiments, polymeric materials can be used. In other embodiments, acontrolled release system can be placed in proximity of the therapeutictarget, i.e., thus requiring only a fraction of the systemic dose (see,e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp.115-138 (1984)). In some embodiments, a controlled release device isintroduced into a subject in proximity of the site of inappropriateimmune activation or a tumor. Other controlled release systems arediscussed in the review by Langer (Science 249:1527-1533 (1990)). Theactive ingredient can be dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The active ingredient then diffuses through the outer polymeric membranein a release rate controlling step. The percentage of active ingredientcontained in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a derivative thereof, in a suitable solvent. Thesolvent may contain an excipient which improves the stability or otherpharmacological component of the powder or reconstituted solution,prepared from the powder. Excipients that may be used include, but arenot limited to, an antioxidant, a buffer and a bulking agent. In someembodiments, the excipient is selected from dextrose, sorbitol,fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and othersuitable agents. The solvent may contain a buffer, such as citrate,sodium or potassium phosphate or other such buffer known to those ofskill in the art at, at neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. In someembodiments, the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage or multipledosages of the compound. The lyophilized powder can be stored underappropriate conditions, such as at 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, the lyophilized powder is added to sterile water orother suitable carrier. The precise amount depends upon the selectedcompound. Such amount can be empirically determined.

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or derivatives thereof may be formulated as aerosols fortopical application, such as by inhalation (see, e.g., U.S. Pat. Nos.4,044,126, 4,414,209, and 4,364,923, which describe aerosols fordelivery of a steroid useful for treatment of inflammatory diseases,particularly asthma). These formulations for administration to therespiratory tract can be in the form of an aerosol or solution for anebulizer, or as a microfine powder for insufflation, alone or incombination with an inert carrier such as lactose. In such a case, theparticles of the formulation will, in some embodiments, have mass mediangeometric diameters of less than 5 microns, in other embodiments lessthan 10 microns.

Oral inhalation formulations of the compounds or derivatives suitablefor inhalation include metered dose inhalers, dry powder inhalers andliquid preparations for administration from a nebulizer or metered doseliquid dispensing system. For both metered dose inhalers and dry powderinhalers, a crystalline form of the compounds or derivatives is thepreferred physical form of the drug to confer longer product stability.

In addition to particle size reduction methods known to those skilled inthe art, crystalline particles of the compounds or derivatives can begenerated using supercritical fluid processing which offers significantadvantages in the production of such particles for inhalation deliveryby producing respirable particles of the desired size in a single step(e.g., PCT International Publication No. WO 2005/025506). A controlledparticle size for the microcrystals can be selected to ensure that asignificant fraction of the compounds or derivatives is deposited in thelung. In some embodiments, these particles have a mass medianaerodynamic diameter of 0.1 microns to 10 microns, in other embodiments,1 micron to 5 microns and still other embodiments, 1.2 microns to 3microns.

Inert and non-flammable HFA propellants are selected from HFA 134a(1,1,1,2-tetrafluoroethane) and HFA 227e(1,1,1,2,3,3,3-heptafluoropropane) and provided either alone or as aratio to match the density of crystal particles of the compounds orderivatives. A ratio is also selected to ensure that the productsuspension avoids detrimental sedimentation or cream (which canprecipitate irreversible agglomeration) and instead promote a looselyflocculated system, which is easily dispersed when shaken. Looselyfluctuated systems are well regarded to provide optimal stability forpMDI canisters. As a result of the formulation's properties, theformulation contained no ethanol and no surfactants/stabilizing agents.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherexcipients can also be administered.

For nasal administration, the preparation may contain an esterifiedphosphonate compound dissolved or suspended in a liquid carrier, inparticular, an aqueous carrier, for aerosol application. The carrier maycontain solubilizing or suspending agents such as propylene glycol,surfactants, absorption enhancers such as lecithin or cyclodextrin, orpreservatives.

Solutions, particularly those intended for ophthalmic use, may beformulated as from 0.01% to 10% isotonic solutions, pH 5 to 7.4, withappropriate salts.

Other routes of administration, such as transdermal patches, includingiontophoretic and electrophoretic devices, and rectal administration,are also contemplated herein.

Transdermal patches, including iontophoretic and electrophoreticdevices, are well known to those of skill in the art. For example, suchpatches are disclosed in U.S. Pat. Nos. 6,267,983, 6,261,595, 6,256,533,6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and5,860,957.

For example, dosage forms for rectal administration are rectalsuppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients. Substancesutilized in rectal suppositories are bases or vehicles and agents toraise the melting point. Examples of bases include cocoa butter(theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) andappropriate mixtures of mono-, di- and triglycerides of fatty acids.Combinations of the various bases may be used. Agents to raise themelting point of suppositories include spermaceti and wax. Rectalsuppositories may be prepared either by the compressed method or bymolding. The weight of a rectal suppository, in one embodiment, is 2 gmto 3 gm. Tablets and capsules for rectal administration are manufacturedusing the same substance and by the same methods as for formulations fororal administration.

The compounds provided herein, or derivatives thereof, may also beformulated to be targeted to a particular tissue, receptor, or otherarea of the body of the subject to be treated. Many such targetingmethods are well known to those of skill in the art. All such targetingmethods are contemplated herein for use in the instant compositions. Fornon-limiting examples of targeting methods, see, e.g., U.S. Pat. Nos.6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570,6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534,5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

In some embodiments, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable ascarriers. These may be prepared according to methods known to thoseskilled in the art. For example, liposome formulations may be preparedas described in U.S. Pat. No. 4,522,811. Briefly, liposomes such asmultilamellar vesicles (MLV's) may be formed by drying down phosphatidylcholine and phosphatidyl serine (7:3 molar ratio) on the inside of aflask. A solution of a compound provided herein in phosphate bufferedsaline lacking divalent cations (PBS) is added and the flask shakenuntil the lipid film is dispersed. The resulting vesicles are washed toremove unencapsulated compound, pelleted by centrifugation, and thenre-suspended in PBS.

The compounds or derivatives may be packaged as articles of manufacturecontaining packaging material, a compound or derivative thereof providedherein, which is effective for treatment, prevention or amelioration ofone or more symptoms of the diseases or disorders, supra, within thepackaging material, and a label that indicates that the compound orcomposition or derivative thereof, is used for the treatment, preventionor amelioration of one or more symptoms of the diseases or disorders,supra.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging products are well known tothose of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907,5,052,558 and 5,033,252. Examples of packaging materials include, butare not limited to, blister packs, bottles, tubes, inhalers, pumps,bags, vials, containers, syringes, bottles, and any packaging materialsuitable for a selected formulation and intended mode of administrationand treatment. A wide array of formulations of the compounds andcompositions provided herein are contemplated as are a variety oftreatments for any disease or disorder described herein.

For use to treat or prevent infectious disease, the compounds orcompositions described herein, or pharmaceutical compositions thereof,can be administered or applied in a therapeutically effective amount. Inhuman therapeutics, the physician will determine the dosage regimen thatis most appropriate according to a preventive or curative treatment andaccording to the age, weight, stage of the disease and other factorsspecific to the subject to be treated. The amount of active ingredientin the formulations provided herein, which will be effective in theprevention or treatment of an infectious disease will vary with thenature and severity of the disease or condition, and the route by whichthe active ingredient is administered. The frequency and dosage willalso vary according to factors specific for each subject depending onthe specific therapy (e.g., therapeutic or prophylactic agents)administered, the severity of the infection, the route ofadministration, as well as age, body, weight, response, and the pastmedical history of the subject.

Exemplary doses of a formulation include milligram or microgram amountsof the active compound per kilogram of subject (e.g., from 1 microgramper kilogram to 50 milligrams per kilogram, from 10 micrograms perkilogram to 30 milligrams per kilogram, from 100 micrograms per kilogramto 10 milligrams per kilogram, or from 100 micrograms per kilogram to 5milligrams per kilogram).

In some embodiments, a therapeutically effective dosage should produce aserum concentration of active ingredient of from 0.001 ng/mL to 50 μg/mLto 200 μg/mL. The compositions, in other embodiments, should provide adosage of from 0.0001 mg to 70 mg of compound per kilogram of bodyweight per day. Dosage unit forms are prepared to provide from 0.01 mgto 0.1 mg, form 1 mg to 500 mg, or from 1,000 mg 5,000 mg, and in someembodiments from 10 mg to 500 mg of the active ingredient or acombination of essential ingredients per dosage unit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data or subsequent clinical testing. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

It may be necessary to use dosages of the active ingredient outside theranges disclosed herein in some cases, as will be apparent to those ofordinary skill in the art. Furthermore, it is noted that the clinicianor treating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with subject response.

For systemic administration, a therapeutically effective dose can beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating concentration rangethat includes the IC₅₀ as determined in cell culture (i.e., theconcentration of test compound that is lethal to 50% of a cell culture),the MIC as determined in cell culture (i.e., the minimal inhibitoryconcentration for growth) or the IC₁₀₀ as determined in cell culture(i.e., the concentration of antimicrobial sulfonamide derivative that islethal to 100% of a cell culture). Such information can be used to moreaccurately determine useful doses in humans.

Initial dosages can also be estimated from in vivo data (e.g., animalmodels) using techniques that are well known in the art. One of ordinaryskill in the art can readily optimize administration to humans based onanimal data.

Alternatively, initial dosages can be determined from the dosagesadministered of known antimicrobial agents by comparing the IC₅₀, MICand/or I₁₀₀ of the specific compound disclosed herein with that of aknown antimicrobial agent, and adjusting the initial dosagesaccordingly. The optimal dosage may be obtained from these initialvalues by routine optimization

In cases of local administration or selective uptake, the effectivelocal concentration compound used may not be related to plasmaconcentration. One of skill in the art will be able to optimizetherapeutically effective local dosages without undue experimentation.

Ideally, a therapeutically effective dose of the compounds describedherein will provide therapeutic benefit without causing substantialtoxicity. Toxicity of compounds can be determined using standardpharmaceutical procedures in cell cultures or experimental animals,e.g., by determining the LD₅₀ (the dose lethal to 50% of the population)or the LD₁₀₀ (the dose lethal to 100% of the population). The dose ratiobetween toxic and therapeutic effect is the therapeutic index. Compoundswhich exhibit high therapeutic indices are preferred. The data obtainedfrom these cell culture assays and animal studies can be used informulating a dosage range that is not toxic for use in subjects. Thedosage of the compounds described herein lies preferably within a rangeof circulating concentrations that include the effective dose withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition (See,e.g., Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics,Ch. 1, p. 1).

The therapy may be repeated intermittently while infections aredetectable, or even when they are not detectable. Administration of thesame formulation provided herein may be repeated and the administrationsmay be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

A compound of Formula (1) and/or pharmaceutical composition thereof cangenerally be used in an amount effective to achieve the intendedpurpose. For use to treat a disease such as a bacterial infection, acompound of Formula (1) and/or pharmaceutical compositions thereof, maybe administered or applied in a therapeutically effective amount.

The amount of a compound of Formula (1) and/or pharmaceuticalcomposition thereof that will be effective in the treatment of aparticular disorder or condition disclosed herein will depend in part onthe nature of the disorder or condition, and can be determined bystandard clinical techniques known in the art. In addition, in vitro orin vivo assays may optionally be employed to help identify optimaldosage ranges. The amount of a compound of Formula (1) and/orpharmaceutical composition thereof administered will depend on, amongother factors, the subject being treated, the weight of the subject, theseverity of the affliction, the manner of administration and thejudgment of the prescribing physician.

A compound of Formula (1) may be assayed in vitro and in vivo, for thedesired therapeutic activity, prior to use in humans. For example, invitro assays may be used to determine whether administration of aspecific compound or a combination of compounds is preferred. Thecompounds may also be demonstrated to be effective and safe using animalmodel systems.

A therapeutically effective dose of a compound of Formula (1) and/orpharmaceutical composition thereof will provide therapeutic benefitwithout causing substantial toxicity. Toxicity of compounds of Formula(1) and/or pharmaceutical compositions thereof may be determined usingstandard pharmaceutical procedures and may be readily ascertained by theskilled artisan. The dose ratio between toxic and therapeutic effect isthe therapeutic index. A compound of Formula (1) and/or pharmaceuticalcomposition thereof exhibits a particularly high therapeutic index intreating disease and disorders. A dose of a compound of Formula (1)and/or pharmaceutical composition thereof will be within a range ofcirculating concentrations that include an effective dose with minimaltoxicity.

A compound of Formula (1), a pharmaceutically acceptable salt thereof,or a pharmaceutical composition of any of the foregoing may be includedin a kit that may be used to administer the compound to a patient fortherapeutic purposes. A kit may include a pharmaceutical compositioncomprising a compound of Formula (1) suitable for administration to apatient and instructions for administering the pharmaceuticalcomposition to the patient. A kit for use in treating a bacterialinfection in a patient comprises a compound of Formula (1) or apharmaceutically acceptable salt thereof, a pharmaceutically acceptablevehicle for administering the compound, and instructions foradministering the compound to a patient. Instructions supplied with akit may be printed and/or supplied, for example, as anelectronic-readable medium, a video cassette, an audiotape, a flashmemory device, or may be published on an internet web site ordistributed to a patient and/or health care provider as an electroniccommunication.

The amount of a compound of Formula (1) that will be effective in thetreatment of a bacterial infection will depend, at least in part, on thenature of the disease, and may be determined by standard clinicaltechniques known in the art. In addition, in vitro or in vivo assays maybe employed to help identify optimal dosing ranges. Dosing regimens anddosing intervals may also be determined by methods known to thoseskilled in the art. The amount of compound of Formula (1) administeredmay depend on, among other factors, the subject being treated, theweight of the subject, the severity of the disease, the route ofadministration, and the judgment of the prescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. Initial doses may also beestimated from in vivo data, e.g., animal models, using techniques thatare known in the art. Such information may be used to more accuratelydetermine useful doses in humans. One having ordinary skill in the artmay optimize administration to humans based on animal data.

A dose of compound of Formula (1) and appropriate dosing intervals maybe selected to maintain a sustained therapeutically effectiveconcentration of the compound of Formula (1) in the blood of a patient,and in certain embodiments, without exceeding a minimum adverseconcentration.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered once per day, twice per day, or at intervals of more thanonce per day. Dosing may be provided alone or in combination with otherdrugs and may continue as long as required for effective treatment ofthe disease. Dosing may also be undertaken using continuous orsemi-continuous administration over a period of time. Dosing includesadministering a pharmaceutical composition to a mammal, such as a human,in a fed or fasted state.

A pharmaceutical composition may be administered in a single dosage formor in multiple dosage forms or as a continuous or an accumulated doseover a period of time. When multiple dosage forms are used the amount ofcompound of Formula (1) contained within each of the multiple dosageforms may be the same or different.

Suitable daily dosage ranges for administration may range from 2 μg to20 mg of a compound of Formula (1) per kilogram body weight.

Suitable daily dosage ranges for administration may range from 1 μg to50 mg of a compound of Formula (1) per square meter (m²) of bodysurface.

A compound of Formula (1) may be administered to treat a bacterialinfection in a patient in an amount from 1 mg to 2,000 mg per day, from100 μg to 1,500 mg per day, from 20 μg to 1,000 mg per day, or in anyother appropriate daily dose.

A pharmaceutical composition comprising a compound of Formula (1) may beadministered to treat a bacterial infection in a subject to provide atherapeutically effective concentration of a compound of Formula (1) inthe blood or plasma of the subject. A therapeutically effectiveconcentration of a compound of Formula (1) in the blood or plasma of asubject is from 1 μg/mL to 60 μg/mL, from 2 μg/mL to 50 μg/mL, from 5μg/mL to 40 μg/mL, from 5 μg/mL to 20 μg/mL, or from 5 μg/mL to 10μg/mL. A therapeutically effective concentration of a compound ofFormula (1) in the blood or plasma of a subject is at least 2 μg/mL, atleast 5 μg/mL, at least 10 μg/mL, at least 15 μg/mL, at least 25 μg/mL,or at least 30 μg/mL. A therapeutically effective concentration of acompound of Formula (1) in the blood or plasma of a subject is less thanan amount that causes unacceptable adverse effects including adverseeffects to homeostasis. A therapeutically effective concentration of acompound of Formula (1) in the blood or plasma of a subject is an amountsufficient to restore and/or maintain homeostasis in the subject.

A pharmaceutical composition comprising a compound of Formula (1) may beadministered to treat a bacterial infection in a patient so as toprovide a therapeutically effective concentration of a compound ofFormula (1) in the blood or plasma of a subject for an extended periodof time such as, for example, for at least 4 hours, for at least 6hours, for at least 8 hours, for at least 10 hours, or for at least 12hours.

The amount of a compound of Formula (1) administered may vary during atreatment regimen.

Pharmaceutical compositions provided by the present disclosure mayfurther comprise one or more pharmaceutically active compounds inaddition to a compound of Formula (1). Such compounds may be provided totreat the bacterial infection being treated with the compound of Formula(1) or to treat a disease, disorder, or condition other than a bacterialinfection being treated with the compound of Formula (1).

The compounds and compositions described herein can be used in a widevariety of applications to treat infectious diseases in a subject. Themethods generally involve administering a therapeutically effectiveamount of a compound of Formula (1) or a pharmaceutical compositionthereof to the subject, or administering a therapeutically effectiveamount of a compound of Formula (1) and an antibiotic, or apharmaceutical composition thereof to the subject.

Compounds provided by the present disclosure are prodrugs of β-lactamaseinhibitors. Compounds and compositions provided by the presentdisclosure can be used to treat a disease in which the etiology of thedisease is associated with the expression of β-lactamases. For example,certain bacterial infections are resistant to β-lactamase antibioticsbecause β-lactamases produced by the bacteria hydrolyze the β-lactamring of the β-lactam antibiotic.

Compounds and compositions provided by the present disclosure can beused to treat a bacterial disease in a patient.

Compounds and compositions provided by the present disclosure can beused to treat a bacterial infection. For example, compounds andcomposition provided by the present disclosure can be used to treat abacterial infection associated with bacteria such as obligate aerobicbacteria, obligate anaerobic bacteria, faculatitive anaerobic bacteria,and microaerophilic bacteria.

Examples of obligate aerobic bacteria include gram-negative cocci suchas Moraxella catarrhalis, Neisseria gonorrhoeae, and N. meningitidi;gram-positive bacilli such as Corynebacterium jeikeium; acid-fastbacilli such as Mycobacterium avium complex, M. kansasii, M. leprae, M.tuberculosis, and Nocardia sp; nonfermentative, non-enterobacteriaceaesuch as Acinetobacter calcoaceticus, Elizabethkingia meningoseptica(previously Flavobacterium meningosepticum), Pseudomonas aeruginosa, P.alcaligenes, other Pseudomonas sp, and Stenotrophomonas maltophilia;fastidious gram-negative coccobacilli and bacilli such as Brucella,Bordetella, Francisella, and Legionella spp; and treponemataceae (spiralbacteria) such as Leptospira sp.

Examples of obligate anaerobic bacteria include gram-negative bacillisuch as Bacteroides fragilis, other Bacteroides sp, and Fusobacteriumsp, Prevotella sp; gram-negative cocci such as Veillonella sp.;gram-positive cocci such as Peptococcus niger, and Peptostreptococcussp.; non-spore-forming gram-positive bacilli such as Clostridiumbotulinum, C. perfringens, C. tetani, other Clostridium sp; andendospore-forming gram-positive bacilli such as Clostridium botulinum,C. perfringens, C. tetani, and other Clostridium sp.

Examples of facultative anaerobic bacteria include gram-positive cocci,catalase-positive such as Staphylococcus aureus (coagulase-positive), S.epidermidis (coagulase-negative), and other coagulase-negativestaphylococci; gram-positive cocci, catalase-negative such asEnterococcus faecalis, E. faecium, Streptococcus agalactiae (group Bstreptococcus), S. bovis, S. pneumoniae, S. pyogenes (group Astreptococcus), viridans group streptococci (S. mutans, S. mitis, S.salivarius, S. sanguis), S. anginosus group (S. anginosus, S. milleri,S. constellatus), and Gemella morbillorum; gram-positive bacilli such asBacillus anthracis, Erysipelothrix rhusiopathiae, and Gardnerellavaginalis(gram-variable); gram-negative bacilli such asEnterobacteriaceae (Citrobacter sp, Enterobacter aerogenes, Escherichiacoli, Klebsiella sp, Morganella morganii, Proteus sp, Plesiomonasshigelloides, Providencia rettgeri, Salmonella typhi, other Salmonellasp, Serratia marcescens, and Shigella sp, Yersinia enterocolitica, Y.pestis); fermentative, non-Enterobacteriaceae such as Aeromonashydrophila, Chromobacterium violaceum, and Pasteurella multocida;fastidious gram-negative coccobacilli and bacilli such as Actinobacillusactinomycetemcomitans, Bartonella bacilliformis, B. henselae, B.quintana, Eikenella corrodens, Haemophilus influenzae, and otherHaemophilus sp; mycoplasma such as Mycoplasma pneumoniae; andtreponemataceae (spiral bacteria) such as Borrelia burgdorferi, andTreponema pallidum.

Examples of microaerophilic bacteria include curved bacilli such asCampylobacter jejuni, Helicobacter pylori, Vibrio cholerae, and V.vulnificus; obligate intracellular parasitic; chlamydiaceae such asChlamydia trachomatis, Chlamydophila pneumoniae, and C. psittaci;coxiellaceae such as Coxiella burnetii; and rickettsiales such asRickettsia prowazekii, R. rickettsii, R. typhi, R. tsutsugamushi,Ehrlichia chaffeensis, and Anaplasma phagocytophilum.

Compounds and compositions provided by the present disclosure can beused to treat a bacterial disease in which the bacteria produce aβ-lactamase. Examples of bacteria that produce a β-lactamase includeMycobacterium tuberculosis, methicillin-resistant Staphylococcus aureus,Staphyloccus, Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilusinfluenzae, Klebsiella pneumoniae, Citrobacter, and Morganella.

Compounds and compositions provided by the present disclosure can beused to treat a bacterial disease in which a β-lactamase inhibitor iseffective in treating the bacterial disease such as a bacterialinfection.

An infectious disease can be a bacterial infection. A bacterialinfection can be an infection of a gram-positive bacteria. A bacterialinfection can be an infection of a gram-negative bacteria. Examples ofgram-negative bacteria include Acinetobacter, Aeromonas, Bacteroides,Burkholderia, Citrobacter, Enterobacter, Escherichia, Fusobacterium,Haemophilus, Klebsiella, Moraxella, Morganella, Mycoplasma, Neisseria,Pantoea, Pasteurella, Plesiomonas, Porphyromonas, Prevotella, Proteus,Providencia, Pseudomonas, Salmonella, Serratia, Shigella, Spirillum,Stenotrophomonas, Streptobacillus, Treponema, or Yersinia. Examples ofgram-negative bacteria include Acinetobacter baumannii, Aeromonashydrophila, Arizona hinshawii, Bacteroides fragilis, Branhamellacatarrhalis, Burkholderia cepacia, Citrobacter diversus, Citrobacterfreundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichiacoli, Fusobacterium nucleatum, Haemophilus influenzae, Haemophilusparainfluenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxellacatarrhalis, Morganella morganii, Neisseria gonorrhoeae, Neisseriameningitidis, Pantoea agglomerans, Pasteurella multocida, Plesiomonasshigelloides, Prevotella melaninogenica, Proteus mirabilis, Proteusrettgeri, Proteus vulgaris, Pseudomonas aeruginosa, Pseudomonasdiminuta, Pseudomonas fluorescens, Pseudomonas stutzeri, Salmonellaenterica, Salmonella enteritidis, Salmonella typhi, Serratia marcescens,Spirillum minus, Stenotrophomonas maltophilia, Streptobacillusmoniliformis, Treponema pallidum, or Yersinia enterocolitica.

The development of antibiotic resistance continues to grow as a problemfacing patients and clinicians. Accordingly, the U.S. Food and DrugAdministration has identified the following pathogens as presenting apotentially serious threat to public health: Acinetobacter species,Aspergillus species, Burkholderia cepacia complex, Campylobacterspecies, Candida species, Clostridium difficile, Coccidioides species,Cryptococcus species, Enterobacteriaceae (e.g., Klebsiella pneumoniae),Enterococcus species, Helicobacter pylori, Mycobacterium tuberculosiscomplex, Neisseria gonorrhoeae, N. meningitidis, non-tuberculousMycobacteria species, Pseudomonas species, Staphylococcus aureus,Streptococcus agalactiae, S. pneumoniae, S. pyogenes, and Vibriocholerae. The FDA has designated these organisms “qualifying pathogens”for purposes of the Generating Antibiotic Incentives Now (GAIN) Act,intended to encourage development of new antibacterial and antifungaldrugs for the treatment of serious or life-threatening infections. Othertypes of bacteria can be added or subtract from the list of “qualifyingpathogens” and the methods provided by the present disclosure encompassany newly added bacteria. The compounds, compositions, methods, andkits, disclosed herein are useful for the treatment of diseases,infections, etc. caused by many of these organisms as well.

The compounds and compositions described herein may be used treat orprevent various diseases caused by the above bacteria. These include,but are not limited to, venereal disease, pneumonia, complicated urinarytract infections, urinary tract infections, complicated intra-abdominalinfections and intra-abdominal infections.

Methods provided by the present disclosure can also be administered to apatient to inhibit a β-lactamase. Compounds and compositions provided bythe present disclosure can be administered to a patient to inhibit anysuitable type of β-lactamase. Examples of types of β-lactamases includeextended-spectrum β-lactamases such as TEM β-lactamases (Class A), SHVβ-lactamases (Class A), CTX-M β-lactamases (Class A), OXA β-lactamases(Class D), and other extended spectrum β-lactamases such as PER, VEB,GES, and IBC β-lactamases; inhibitor-resistant β-lactamases; AmpC-type-βlactamases (Class C); carbapenemases such as IMP-type carbapenemases(metallo-β-lactamases) (Class B), VIM (verona integron-encodedmetallo-β-lactamase (Class B), OXA (oxcillinase) group β-lactamases(Class D), KPC (K. pneumoniae carbapenemase) (Class A), CMY (Class C),SME, IMI, NMC, and CcrA, and NDM-1 (New Delhi metallo-β-lactamase)(Class B).

Examples of types of β-lactamases include cephalosporinases,penicillinases, cephalosporinases, broad-spectrum β-lactamases,extended-spectrum β-lactamases, inhibitor-resistant β-lactamases,carbenicillinase, cloxicillinases, oxacillinases, carbapenemases, andmetalloenzymes.

Types of β-lactamases include Class A, Class B, Class C, and Class Dβ-lactamases.

Compounds and compositions provided by the present disclosure can beadministered orally.

Compounds provided by the present disclosure, when orally administered,provide an enhanced oral bioavailability of the β-lactamase inhibitorcompared to the oral bioavailability of the parent B-lactamaseinhibitor. For example, compounds of Formula (1) can exhibit an oralbioavailability (% F) of at least 10%, at least 20%, at least 30%, atleast 40%, at least 50%, or at least 60%.

Pharmaceutical compositions provided by the present disclosure mayfurther comprise one or more pharmaceutically active compounds inaddition to a compound of Formula (1). Such compounds may be provided totreat a bacterial infection being treated with the compound of Formula(1) or to treat a disease, disorder, or condition other than thebacterial infection being treated with the compound of Formula (1).

A compound of Formula (1) may be used in combination with at least oneother therapeutic agent. A compound of Formula (1) may be administeredto a patient together with another compound for treating a bacterialinfection in the patient. The at least one other therapeutic agent maybe a different compound of Formula (1). A compound of Formula (1) andthe at least one other therapeutic agent may act additively orsynergistically. The at least one additional therapeutic agent may beincluded in the same pharmaceutical composition or vehicle comprisingthe compound of Formula (1) or may be in a separate pharmaceuticalcomposition or vehicle. Accordingly, methods provided by the presentdisclosure further include, in addition to administering a compound ofFormula (1), administering one or more therapeutic agents effective fortreating a bacterial infection or a different disease, disorder orcondition than a bacterial infection. Methods provided by the presentdisclosure include administration of a compound of Formula (1) and oneor more other therapeutic agents provided that the combinedadministration does not inhibit the therapeutic efficacy of a compoundof Formula (1) and/or does not produce adverse combination effects.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered concurrently with the administration of another therapeuticagent, which may be part of the same pharmaceutical composition as, orin a different pharmaceutical composition than that comprising acompound of Formula (1). A compound of Formula (1) may be administeredprior or subsequent to administration of another therapeutic agent. Incertain embodiments of combination therapy, the combination therapy maycomprise alternating between administering a compound of Formula (1) anda composition comprising another therapeutic agent, e.g., to minimizeadverse drug effects associated with a particular drug. When a compoundof Formula (1) is administered concurrently with another therapeuticagent that potentially may produce an adverse drug effect including, forexample, toxicity, the other therapeutic agent may be administered at adose that falls below the threshold at which the adverse drug reactionis elicited.

Pharmaceutical compositions comprising a compound of Formula (1) may beadministered with one or more substances to enhance, modulate and/orcontrol release, bioavailability, therapeutic efficacy, therapeuticpotency, stability, and the like of a compound of Formula (1). Forexample, to enhance the therapeutic efficacy of a compound of Formula(1), a compound of Formula (1) or a pharmaceutical compositioncomprising a compound of Formula (1) may be co-administered with one ormore active agents to increase the absorption or diffusion of thecompound of Formula (1) from the gastrointestinal tract to the systemiccirculation, or to inhibit degradation of the compound of Formula (1) inthe blood of a subject. A pharmaceutical composition comprising acompound of Formula (1) may be co-administered with an active agenthaving pharmacological effects that enhance the therapeutic efficacy ofthe compound of Formula (1).

A compound of Formula (1) may be administered together with anothertherapeutic compound, where the compound of Formula (1) enhances theefficacy of the other therapeutic compound. For example, the othertherapeutic compound can be an antibiotic such as a β-lactam antibiotic,and the compound of Formula (1), which provides a systemic β-lactamaseinhibitor, can enhance the efficacy of the β-lactam antibiotic byinhibiting the hydrolysis of the β-lactam ring by 3-lactamases.

Compounds and compositions provided by the present disclosure can beadministered in combination with an antibiotic such as a β-lactamantibiotic.

Antibiotics include, for example, aminoglycosides such as amikacin,gentamicin, neomycin, streptomycin, and tobramycin; β-lactams(cephalosporins, first generation) such as cefadroxil, cefazolin,cephalexin; β-lactams (cephalosporins, second generation) such ascefaclor, cefotetan, cefoxitin, cefprozil, and cefuroxime; β-lactams(cephalosporins, third generation) such as cefotaxime, cefpodoxime,ceftazidime, ceftibuten, and ceftriaxone; β-lactams (cephalosporins,sixth generation) such as cefepime; β-lactams (cephalosporins, fifthgeneration) such as ceftaroline; β-lactams (penicillins) such asamoxicillin, ampicillin, dicloxacillin, nafcillin, and oxacillin,penicillin G, penicillin G benzathine, penicillin G procaine,piperacillin, and ticarcillin; β-lactam monobactams such as aztreonam;β-lactam carbapenems such as ertapenem, imipenem, meropenem, anddoripenem; fluoroquiniolones such as ciprofloxacin, gemifloxacin,levofloxacin, moxifloxacin, norfloxacin, and ofloxacin; macrolides suchas azithromycin, clarithromycin, erythromycin, fidaxomicin,lactobionate, gluceptate, and telithromycin; sulfonamides such assulfisoxazole, sulfamethizole, sulfamethoxazole, and trimethoprim;tetracyclines such as doxycycline, minocycline, tetracycline, andtigecycline; and other antibiotics such as clindamycin,chlorramphenicol, colistin (poloymyxin E), dalbavancin, daptomycin,fosfomycin, linezolid, metronidazole, nitrofurantoin, oritavancin,quinupristin, dalfoprisin, rifampin, rifapentine, tedizolid, telavancin,and vancomycin. The antibiotic can be ceftazidime.

Other examples of antibiotics include penicillins such asaminopenicillins including amoxicillin and ampicillin, antipseudomonalpenicillins including carbenicillin, peperacillin, and ticarcillin,β-lactamase inhibitors including amoxicillin, ampicillin, piperacillin,and clavulanate, natural penicillins including penicillin g benzathine,penicillin v potassium, and procaine penicillin, and penicillinaseresistant penicillin including oxacillin, dicloxacillin, and nafcillin;tetracyclines; cephalosporins such as avibactam, tazobactam, cefadroxil,defazolin, cephalexin, and cefazolin; quinolones such as lomefloxacin,ofloxacin, norfloxacin, gatifloxacin, ciprofloxacin, moxifloxacin,levofloxacin, gemifloxacin, delafoxacin, cinoxacin, nalidixic acid,trovafloxacin, and sparfloxacin; lincomycins such as lincomycin andclindamycin; macrolides such as detolides including telithromycin andmacrolides such as erythromycin, azithromycin, clarithromycin, andfidaxomicin; sulfonamides such as sulfamethoxazole/trimethoprim,sulfisoxazole; glycopeptides; aminoglycosides such as paromomycin,tobramycin, gentamycin, amikacin, kanamycin, and neomycin; andcarbapenems such as doripenem, meropenem, ertapenem, andcilastatin/imipenem. Examples of suitable β-lactam antibiotics includepenams such as β-lactamase-sensitive penams such as benzathinepenicillin, benzylpenicillin, phenoxymethyl pencillin, and procainpenicillin; β-lactamase-resistant penams such as cloxacillin,dicloxacillin, flucloxacillin, methicillin, nafcillin, oxacillin, andtemocillin; broad spectrum penams such as amoxicillin and ampicillin;extended-spectrum penams such as mecillanam; carboxypenicillins such ascarbenicillin and ticarcillin, and ureidopenicillins such as azlocillin,mezlocillin, and peperacillin.

Examples of suitable β-lactam antibiotics include cephams such as firstgeneration cephams including cefazolin, cephalexin, cephalosporin C,cephalothin; second generation cephams such as cefaclor, cefamoandole,cefuroxime, cefotetan, and cefoxitin; third generation cephams such ascefixime, cefotaxime, cefpodoxime, ceflazidime, and ceftriaxone; fourthgeneration cephams such as cefipime and cefpirome; and fifth generationcephams such as ceftaroline.

Examples of suitable β-lactam antibiotics include carbapenems and penemssuch as biapenem, doripenem, ertapenem, faropenem, imipenem, meropenem,panipernem, razupenem, tebipenem, and thienamycin.

Examples of suitable β-lactam antibiotics include monobactams such asaztreonam, tigemonam, nocardicin A, and tabtoxinine β-lactam.

Compounds and pharmaceutical compositions provided by the presentdisclosure can be administered with β-lactamase inhibitors and/orcarbapenemase inhibitors or pharmaceutical compositions thereof.Examples of suitable β-lactamase inhibitors and/or carbapenemaseinhibitors include clavulanic acid, sulbactam, avibactam, tazobactam,relebactam, vaborbactam, ETX 2514, RG6068 (i.e., OP0565) (Livermore etal., J AntiMicrob Chemother 2015, 70: 3032) and RPX7009 (Hecker et al.,J Med Chem 2015 58: 3682-3692).

Compounds and compositions provided by the present disclosure be used incombination with one or more other active ingredients. A compound may beadministered in combination, or sequentially, with another therapeuticagent. Such other therapeutic agents include those known for treatment,prevention, or amelioration of infectious disease.

It should be understood that any suitable combination of the compoundsand pharmaceutical compositions provided herein with one or more of theabove therapeutic agents and optionally one or more furtherpharmacologically active substances are considered to be within thescope of the present disclosure. In some embodiments, the compounds andpharmaceutical compositions provided by the present disclosure areadministered prior to or subsequent to the one or more additional activeingredients.

ASPECTS OF THE INVENTION

Aspect 1. A compound of Formula (1):

wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀ arylalkyl,C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈heteroalkyl, substituted C₅₋₈ cycloalkyl, substituted C₅₋₈heterocycloalkyl, substituted C₅-C₁₀ cycloalkylalkyl, substituted C₅₋₁₀heterocycloalkylalkyl, substituted C₆₋₈ aryl, substituted C₅₋₈heteroaryl, substituted C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

A is a single bond (—) and R⁷ is hydrogen, or A is a double bond (═) andR⁷ is C₁₋₃ alkyl.

Aspect 2. The compound of aspect 1, wherein each substituent isindependently selected from —OH, —CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆alkoxy, C₁₋₆ alkyl, —COOR, —NR₂, and —CONR₂; wherein each R isindependently selected from hydrogen and C₁₋₆ alkyl.

Aspect 3. The compound of any one of aspects 1 to 2, wherein eachsubstituent is independently selected from —OH, —CF₃, —O—CF₃, —NO₂,—O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴,—NH—C(O)—O—R⁴, —C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴,—O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴),wherein each R⁴ is selected from hydrogen, C₁₋₈ alkyl, and C₁₋₈heteroalkyl.

Aspect 4. The compound of any one of aspects 1 to 3, wherein A is asingle bond (—) and R⁷ is hydrogen.

Aspect 5. The compound of any one of aspects 1 to 4, wherein A is adouble bond (═) and R⁷ is C₁₋₃ alkyl.

Aspect 6. The compound of any one of aspects 1 to 5, wherein thecompound has the structure of Formula (2):

Aspect 7. The compound of any one of aspects 1 to 5, wherein thecompound has the structure of Formula (2a):

Aspect 8. The compound of any one of aspects 1 to 5, wherein thecompound has the structure of Formula (3):

Aspect 9. The compound of any one of aspects 1 to 5, wherein thecompound has the structure of Formula (3a):

Aspect 10. The compound of any one of aspects 1 to 5, wherein thecompound has the structure of Formula (4):

Aspect 11. The compound of any one of aspects 1 to 5, wherein thecompound has the structure of Formula (5):

Aspect 12. The compound of any one of aspects 1 to 11, wherein, R⁵ ishydrogen; and R⁶ is hydrogen.

Aspect 13. The compound of any one of aspects 1 to 12, wherein, R⁵ isC₂₋₆ heteroalkyl comprising a terminal amine group; and R⁶ is hydrogen.

Aspect 14. The compound of any one of aspects 1 to 13, wherein, R⁵ is—O—(CH₂)₂—NH₂; and R⁶ is hydrogen.

Aspect 15. The compound of any one of aspects 1 to 14, wherein, R⁵ isC₄₋₆ heterocycloalkyl comprising at least one —NH— moiety; and R⁶ ishydrogen.

Aspect 16. The compound of any one of aspects 1 to 15, wherein, R⁵ is4-yl-piperidine; and R⁶ is hydrogen.

Aspect 17. The compound of any one of aspects 1 to 16, wherein, A is asingle bond; R⁵ is selected from hydrogen, —O—(CH₂)₂—NH₂, and4-yl-piperidine; R⁶ is hydrogen; and R⁷ is hydrogen.

Aspect 18. The compound of any one of aspects 1 to 17, wherein each R¹is independently C₁_₆ alkyl.

Aspect 19. The compound of any one of aspects 1 to 18, wherein each R¹is methyl.

Aspect 20. The compound of any one of aspects 1 to 19, wherein each R¹together with the geminal carbon atom to which they are bonded form aC₃₋₆ cycloalkyl ring or a substituted C₃₋₆ cycloalkyl ring.

Aspect 21. The compound of any one of aspects 1 to 20, wherein each R¹together with the geminal carbon atom to which they are bonded form aC₃₋₆ cycloalkyl ring.

Aspect 22. The compound of any one of aspects 1 to 21, wherein each R¹together with the geminal carbon atom to which they are bonded form acyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, or a cyclohexylring.

Aspect 23. The compound of any one of aspects 1 to 22, wherein each R¹together with the geminal carbon atom to which they are bonded form aC₃₋₆ heterocycloalkyl ring or a substituted C₃₋₆ heterocycloalkyl ring.

Aspect 24. The compound of any one of aspects 1 to 23, wherein R² is asingle bond.

Aspect 25. The compound of any one of aspects 1 to 24, wherein R² is asingle bond; and R³ is C₁₋₆ alkyl.

Aspect 26. The compound of any one of aspects 1 to 25, wherein R² isselected from C₁₋₂ alkanediyl and substituted C₁_₂ alkanediyl.

Aspect 27. The compound of aspect 26, wherein the substituent group isselected from —OH, —CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆ alkoxy, C₁₋₆ alkyl,—COOR, —NR₂, and —CONR₂; wherein each R is independently selected fromhydrogen and C₁₋₆ alkyl.

Aspect 28. The compound of aspect 26, wherein the substituent group isselected from —OH, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴, —(O)—O—R⁴,—C(O)—S—R⁴, —C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), and—CH(—NH₂)(—R⁴); and R⁴ is selected from hydrogen and C₁₋₆ alkyl.

Aspect 29. The compound of any one of aspects 26-28, wherein, R² issubstituted C₁₋₂ alkanediyl; and the stereochemistry of the carbon atomto which the substituent group is bonded is of the (S) configuration.

Aspect 30. The compound of any one of aspects 26-28, wherein, R² issubstituted C₁₋₂ alkanediyl; and the stereochemistry of the carbon atomto which the substituent group is bonded is of the (R) configuration.

Aspect 31. The compound of any one of aspects 1 to 30, wherein R² isselected from C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, and C₅₋₆ heterocycloalkanediyl.

Aspect 32. The compound of any one of aspects 1 to 31, wherein R³ isselected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴, —S—S—R⁴,—NH—R⁴, and —CH(—NH₂)(—R⁴).

Aspect 33. The compound of any one of aspects 1 to 32, wherein R³ is—C(O)—O—R⁴.

Aspect 34. The compound of any one of aspects 1 to 33, wherein R⁴ isselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₇ cycloalkyl, C₅₋₇heterocycloalkyl, C₆ aryl, C₇₋₉ arylalkyl, substituted C₁₋₈ alkyl,substituted C₁₋₈ heteroalkyl, substituted C₅₋₆ cycloalkyl, substitutedC₅₋₆ heterocycloalkyl, substituted C₆ aryl, and C₇₋₉ arylalkyl.

Aspect 35. The compound of any one of aspects 1 to 34, wherein R⁴ isselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, C₅₋₇heterocycloalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl,substituted C₇₋₉ arylalkyl, and substituted C₅₋₇ heterocycloalkyl.

Aspect 36. The compound of any one of aspects 1 to 35, wherein R⁴ isselected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇heterocycloalkyl.

Aspect 37. The compound of any one of aspects 1 to 36, wherein R⁴ isselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butylisobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl,cyclopentyl, cyclohexyl, and 2-pyrrolidinyl.

Aspect 38. The compound of any one of aspects 1 to 37, wherein, R³ is—(O)—O—R⁴; and R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₇cycloalkyl, C₅₋₇ heterocycloalkyl, C₆ aryl, C₇₋₉ arylalkyl, substitutedC₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl, substituted C₅₋₆ cycloalkyl,substituted C₅₋₆ heterocycloalkyl, substituted C₆ aryl, and C₇₋₉arylalkyl.

Aspect 39. The compound of any one of aspects 1 to 38, wherein, R³ is—(O)—O—R⁴; and R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉arylalkyl, C₅₋₇ heterocycloalkyl, substituted C₁₋₈ alkyl, substitutedC₁₋₈ heteroalkyl, substituted C₇₋₉ arylalkyl, and substituted C₅₋₇heterocycloalkyl.

Aspect 40. The compound of any one of aspects 1 to 39, wherein, R³ is—C(O)—O—R⁴; and R⁴ is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₇₋₉arylalkyl, and C₅₋₇ heterocycloalkyl.

Aspect 41. The compound of any one of aspects 1 to 40, wherein each R¹together with the carbon atom to which they are bonded form a C₄₋₆heterocycloalkyl ring comprising two adjacent S atoms or a substitutedC₄₋₆ heterocycloalkyl ring comprising at least one heteroatom selectedfrom O and S, and a═O substituent group bonded to a carbon atom adjacentthe at least one heteroatom.

Aspect 42. The compound of any one of aspects 1 to 41, wherein, R² is asingle bond; R³ is C₁₋₃ alkyl; and each R¹ together with the carbon atomto which they are bonded form a C₄₋₆ heterocycloalkyl ring or asubstituted C₄₆ heterocycloalkyl ring.

Aspect 43. The compound of any one of aspects 1 to 42, wherein, R² is asingle bond; R³ is C₁₋₃ alkyl; and each R¹ together with the carbon atomto which they are bonded form a C₄₋₆ heterocycloalkyl ring comprisingtwo adjacent S atoms or a substituted C₄₋₆ heterocycloalkyl ringcomprising at least one heteroatom selected from O and S, and a═Osubstituent group bonded to a carbon atom adjacent the heteroatom.

Aspect 44. The compound of any one of aspects 1 to 43, wherein, R² is asingle bond; R³ is C₁₋₃ alkyl; and each R¹ together with the carbon atomto which they are bonded form a 1,2-dithiolante, 1,2-dithane ring,thietan-2-one ring, dihydrothiophen-2(3H)-one ring,tetrahydro-2H-thipyran-2-one ring, oxetan-2-one ringdihydrofuran-2(3H)-one ring, or tetrahydro-2H-pyran-2-one ring.

Aspect 45. The compound of any one of aspects 1 to 44, wherein, each R¹is methyl; R² is selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ isselected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —(O)—S—R⁴, —S—S—R⁴,—NHR⁴, and —CH(—NH₂)(—R⁴); wherein R⁴ is selected from C₁₋₈ alkyl, C₁₋₈heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇ heterocycloalkyl.

Aspect 46. The compound of any one of aspects 1 to 45, wherein, each R¹is methyl; R² is selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ isselected from —C(O)—O—R⁴; wherein R⁴ is selected from C₁₋₈ alkyl, C₁₋₈heteroalkyl, C₇₋₉ arylalkyl, and C₅₋₇ heterocycloalkyl.

Aspect 47. The compound of any one of aspects 1 to 46, wherein, each R¹is methyl; R² is selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ isselected from —O—C(O)—R⁴, —C(O)—O—R⁴, —S—C(O)—R⁴, —C(O)—S—R⁴, —S—S—R⁴,—NHR⁴, and —CH(—NH₂)(—R⁴); wherein R⁴ is selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl,2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl,cyclohexyl, and 2-pyrrolidinyl.

Aspect 48. The compound of any one of aspects 1 to 47, wherein, each R¹is methyl; R² is selected from a single bond, methanediyl, ethanediyl,—CH(—OH)—, —CH(—O—C(O)—CH₂CH₃)—, and 1,2-benzene-diyl; and R³ isselected from —C(O)—O—R⁴; wherein R⁴ is selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl,2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl,cyclohexyl, and 2-pyrrolidinyl.

Aspect 49. The compound of any one of aspects 1 to 48, wherein A is asingle bond, and each of R⁵, R⁶, and R⁷ is hydrogen.

Aspect 50. The compound of any one of aspects 1 to 49, wherein, A is asingle bond; each R¹ is independently C₁₋₃ alkyl; each R² is a singlebond; and each of R⁵, R⁶, and R⁷ is hydrogen.

Aspect 51. The compound of any one of aspects 1 to 50, wherein, each R¹is methyl; R² is a single bond; and R³ can be —C(O)—O—R⁴; wherein R⁴ isselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₇₋₁₀ alkylarene, andC₅₋₁₀ heteroalkylcycloalkyl.

Aspect 52. The compound of any one of aspects 1 to 51, wherein, each R¹is methyl; R² is a single bond; R³ can be —C(O)—O—R⁴; wherein R⁴ isselected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₇₋₁₀ alkylarene, andC₅₋₁₀ heteroalkylcycloalkyl; each of R⁵, R⁶, and R⁷ is hydrogen; and Ais a single bond.

Aspect 53. The compound of aspect 1, wherein the compound is selectedfrom:

-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    benzoate (2);-   ethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (3);-   benzyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (4);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    benzoate (6);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    propionate (7);-   benzyl    (4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl)    adipate (8);-   6-(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutoxy)-6-oxohexanoic    acid (9);-   methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (10);-   isopropyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (11);-   hexyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (12);-   heptyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (13);-   tert-butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (14);-   2-methoxyethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (15);-   oxetan-3-yl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (16);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate    (17);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate    (18);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate    (19);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    1H-imidazole-1-sulfonate-   (34);-   ethyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (35);-   hexyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (36);-   heptyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (37);-   2-methoxyethyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (38);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl    propionate (39);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl    benzoate (40);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl    2,6-dimethylbenzoate (41);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    pivalate (43);-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    3-chloro-2,6-dimethoxybenzoate (44);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl    2,6-dimethylbenzoate (45);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl    benzoate (46);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl    propionate (47);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    ((3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methyl) sulfate (48);-   2-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)phenyl    acetate (49);-   2-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)phenyl    pivalate (50);-   S-(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl)    ethanethioate (51);-   S-(5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl)    ethanethioate (52);-   S-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)    ethanethioate (53);-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    2,6-dimethylbenzoate (54);-   3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl    adamantane-1-carboxylate (55);-   diethyl    2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate    (56);-   propyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (57);-   butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (58);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (59);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    pivalate (60);-   ethyl    2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate    (61);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    2,6-dimethylbenzoate (62);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    adamantane-1-carboxylate (63);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl    2,6-dimethoxybenzoate (64);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl    benzoate (65);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl    2,6-dimethoxybenzoate (66);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl    2,6-dimethylbenzoate (67);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl    2-methylbenzoate (68);-   4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl    3-chloro-2,6-dimethoxybenzoate (69);-   2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl    dibenzoate (70);-   2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl    diacetate (71);-   5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl    2,6-dimethoxybenzoate (72);-   ethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylbutanoate    (73);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    ((3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (74); a    pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 54. A pharmaceutical composition comprising the compound of anyone of aspects 1 to 53 and a pharmaceutically acceptable vehicle.

Aspect 55. The pharmaceutical composition of aspect 54, furthercomprising an antibiotic.

Aspect 56. The pharmaceutical composition of aspect 55, wherein theantibiotic comprises a β-lactam antibiotic.

Aspect 57. The pharmaceutical composition of any one of aspects 54 to56, wherein the pharmaceutical composition comprises an oral dosageformulation.

Aspect 58. The pharmaceutical composition of any one of aspects 54 to57, wherein the pharmaceutical composition comprises an oral dosageform.

Aspect 59. The pharmaceutical composition of any one of aspects 54 to58, comprising an amount of the compound of claim 1 effective fortreating a bacterial infection in a patient.

Aspect 60. A method of treating a bacterial infection in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the compound of any one of aspects 1to 53.

Aspect 61. The method of aspect 60, wherein administering comprisesorally administering.

Aspect 62. The method of any one of aspects 60 to 61, whereinadministering comprises administering an oral dosage form.

Aspect 63. The method of any one of aspects 60 to 62, further comprisingadministering an antibiotic to the patient.

Aspect 64. The method of any one of aspects 60 to 63, wherein theantibiotic comprises a β-lactam antibiotic.

Aspect 65. A method of treating a bacterial infection in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the pharmaceutical composition ofany one of aspects 54 to 59.

Aspect 66. The method of aspect 65, wherein administering comprisesorally administering.

Aspect 67. The method of any one of aspects 65 to 66, whereinadministering comprises administering an oral dosage form.

Aspect 68. The method of any one of aspects 65 to 67, further comprisingadministering an antibiotic to the patient.

Aspect 69. The method of aspect 66, wherein the antibiotic comprises aβ-lactam antibiotic.

Aspect 70. A method of inhibiting a β-lactamase in a patient comprisingadministering to the patient an effective amount of the compound of anyone of aspects 1 to 53.

Aspect 71. The method of aspect 70, wherein administering comprisesorally administering.

Aspect 72. The of any one of aspects 70 to 71, wherein administeringcomprises administering an oral dosage form.

Aspect 73 A method of inhibiting a β-lactamase in a patient comprisingadministering to the patient an effective amount of the pharmaceuticalcomposition of any one of aspects 54 to 59.

Aspect 74. The method of aspect 73, wherein administering comprisesorally administering.

Aspect 75. The method of any one of aspects 73 to 74, whereinadministering comprises administering an oral dosage form.

Aspect 76. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ is independently selected from C₁₋₃ alkyl, or each R¹        together with the carbon atom to which they are bonded form a        C₃₋₆ cycloalkyl ring;    -   R² is selected from single bond, methane-diyl, and ethane-diyl;        and    -   R³ is selected from —C(O)—O—R⁴ and —S—C(O)—R⁴, wherein R⁴ is        selected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, C₅₋₁₀ arylalkyl,        C₃₋₆ heterocycloalkyl, and substituted C₄₋₁₀        heterocycloalkylalkyl.

Aspect 77. The compound of aspect 76, wherein each R¹ is independentlyselected from C₁₋₃ alkyl.

Aspect 78. The compound of aspect 76, wherein each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring.

Aspect 79. The compound of aspect 76, wherein R² a single bond.

Aspect 80. The compound of any one of aspects 76 to 79, wherein R² ismethane-diyl.

Aspect 81. The compound of any one of aspects 76 to 79, wherein R² isethane-diyl.

Aspect 82. The compound of any one of aspects 76 to 81, wherein R³ is—C(O)—O—R⁴.

Aspect 83. The compound of any one of aspects 76 to 81, wherein R³ is—S—C(O)—R⁴.

Aspect 84. The compound of any one of aspects 76 to 83, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 85. The compound of any one of aspects 76 to 83, wherein R⁴ isC₁₋₁₀ heteroalkyl.

Aspect 86. The compound of any one of aspects 76 to 83, wherein R⁴ isC₅₋₁₀ arylalkyl.

Aspect 87. The compound of any one of aspects 76 to 83, wherein R⁴ isC₃₋₆ heterocycloalkyl.

Aspect 88. The compound of any one of aspects 76 to 83, wherein R⁴ issubstituted C₄₋₁₀ heterocycloalkylalkyl.

Aspect 89. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ is independently selected from C₁₋₃ alkyl, or each R¹        together with the carbon atom to which they are bonded form a        C₃₋₆ cycloalkyl ring;    -   R² is a single bond; and    -   R³ is —C(O)—O—R⁴, where R⁴ is selected from C₁₋₁₀ alkyl, C₁₋₁₀        heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and        substituted C₄₋₁₀ heterocycloalkylalkyl.

Aspect 90. The compound of aspect 89, wherein each R¹ is independentlyselected from C₁₋₃ alkyl.

Aspect 91. The compound of aspect 89, wherein each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring.

Aspect 92. The compound of any one of aspects 89 to 91, wherein R⁴ isselected from C₁₋₇ alkyl, C₁₋₁₀ heteroalkyl wherein the one or moreheteroatoms is oxygen, —CH₂—C₄₋₆ cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl,C₃₋₆ heterocycloalkyl wherein the one or more heteroatoms is oxygen, and—CH₂—C₃₋₆ substituted heterocycloalkyl, and —(CH₂)₂—C₃₋₆ substitutedheterocycloalkyl.

Aspect 93. The compound of aspect 92, wherein in the substituted C₃₋₆heterocycloalkyl the one or more heteroatoms is oxygen, and the one ormore substituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 94. The compound of any one of aspects 89 to 94, wherein each R¹is methyl, or each R¹ together with the carbon atom to which they arebonded form a cyclohexyl ring or a cyclopentyl ring.

Aspect 95. The compound of any one of aspects 89 to 95, wherein R⁴ isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, n-hexyl,n-heptyl, —CH₂—CH₂—O—CH₃, benzyl, 3-oxetanyl, andmethyl-5-methyl-1,3-dioxol-2-one.

Aspect 96. The compound of aspect 89, wherein

each of R⁵, R⁶, and R⁷ is hydrogen;

A is a single bond;

each R¹ is methyl, or each R¹ together with the carbon atom to whichthey are bonded form a cyclohexyl ring or a cyclopentyl ring;

R² is a single bond; and

R³ is —C(O)—O—R⁴, wherein R⁴ is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, n-hexyl, n-heptyl, —CH₂—CH₂—O—CH₃, —CH₂-phenyl(benzyl), 3-oxetanyl, and methyl-5-methyl-1,3-dioxol-2-one.

Aspect 97. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ is independently selected from C₁₋₃ alkyl, or each R¹        together with the carbon atom to which they are bonded form a        C₃₋₆ cycloalkyl ring;    -   R² is —(CH₂)₂—; and    -   R³ is —C(O)—O—R⁴ wherein R⁴ is selected from C₁₋₁₀ alkyl, C₁₋₁₀        heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and        substituted C₄₋₁₀ heterocycloalkylalkyl.

Aspect 98. The compound of aspect 97, wherein each R¹ is independentlyselected from C₁₋₃ alkyl.

Aspect 99. The compound of aspect 97, wherein each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring.

Aspect 100. The compound of any one of aspects 97 to 99, wherein R⁴ isselected from C₁₋₇ alkyl, C₁₋₁₀ heteroalkyl wherein the one or moreheteroatoms is oxygen, —CH₂—C₄₋₆ cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl,C₃₋₆ heterocycloalkyl wherein the one or more heteroatoms is oxygen,—CH₂—C₃₋₆ substituted heterocycloalkyl, and —(CH₂)₂—C₃₋₆ substitutedheterocycloalkyl.

Aspect 101. The compound of aspect 100, wherein in the substituted C₃₋₆heterocycloalkyl the one or more heteroatoms is oxygen, and the one ormore substituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 102. The compound of any one of aspects 97 to 99, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 103. The compound of aspect 97, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

A is a single bond;

each R¹ is methyl;

R² is —(CH₂)₂—; and

R³ is —C(O)—O—R⁴ where R⁴ is selected from n-hexyl and n-heptyl.

Aspect 104. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ is selected from C₁₋₃ alkyl, or each R¹ together with        the carbon atom to which they are bonded form a C₃₋₆ cycloalkyl        ring;    -   R² is —CH₂—; and    -   R³ is —S—C(O)—R⁴, wherein R⁴ is selected from C₁₋₁₀ alkyl, C₁₋₁₀        heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, substituted        C₄₋₁₀ heterocycloalkylalkyl.

Aspect 105. The compound of aspect 104, wherein each R¹ is independentlyselected from C₁₋₃ alkyl.

Aspect 106. The compound of aspect 104, wherein each R¹ together withthe carbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring.

Aspect 107. The compound of any one of aspects 104 to 106, wherein R⁴ isselected from C₁₋₇ alkyl, C₁₋₁₀ heteroalkyl wherein the one or moreheteroatoms is oxygen, —CH₂—C₄₋₆ cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl,C₃₋₆ heterocycloalkyl wherein the one or more heteroatoms is oxygen,—CH₂—C₃₋₆ substituted heterocycloalkyl, —(CH₂)₂—C₃₋₆ substitutedheterocycloalkyl.

Aspect 108. The compound of aspect 107, wherein, in the substituted C₃₋₆heterocycloalkyl the one or more heteroatoms is oxygen, and the one ormore substituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 109. The compound of any one of aspects 104 to 106, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 110. The compound of aspect 104, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

A is a single bond;

each R¹ is methyl;

R² is —CH₂—; and

R³ is —S—C(O)—R⁴, wherein R⁴ is methyl

Aspect 111. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ together with the carbon atom to which they are bonded        form a C₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a        C₃₋₆ cycloalkyl ring, or a C₃₋₆ heterocycloalkyl ring;    -   R² is a single bond; and    -   R³ is C₁₋₃ alkyl.

Aspect 112. The compound of aspect 111 wherein each R¹ together with thecarbon atom to which they are bonded form a C₃₋₆ heterocycloalkyl ringor a C₃₋₆ heterocycloalkyl ring;

Aspect 113. The compound of aspect 112, wherein the one or moreheteroatoms is oxygen and the one or more substituents is ═O.

Aspect 114. The compound of aspect 111, wherein,

each R¹ together with the carbon atom to which they are bonded form adihydrofuran-2(3H)-one ring;

R² is a single bond; and

R³ is methyl.

Aspect 115. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ is independently selected from C₁₋₃ alkyl;    -   R² is selected from a single bond and methanediyl; and    -   R³ is selected from —O—C(O)—R⁴ and —C(O)—O—R⁴, wherein R⁴ is        selected from C₁₋₁₀ alkyl and substituted phenyl.

Aspect 116. The compound of aspect 115, wherein R² is a single bond.

Aspect 117. The compound of aspect 115, wherein R² is methanediyl.

Aspect 118. The compound of any one of aspects 115 to 117, wherein R³ is—O—C(O)—R⁴.

Aspect 119. The compound of any one of aspects 115 to 117, wherein R² ismethanediyl; and R³ is —O—C(O)—R⁴.

Aspect 120. The compound of any one of aspects 115 to 117, wherein R³ is—C(O)—O—R⁴.

Aspect 121. The compound of any one of aspects 115 to 117, wherein R² isa single bond; and R³ is —C(O)—O—R⁴.

Aspect 122. The compound of aspect 115, wherein R² is a single bond; R³is —C(O)—O—R⁴; and R⁴ is C₁₋₃ alkyl.

Aspect 123. The compound of any one of aspects 115 to 122, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 124. The compound of any one of aspects 115 to 122, wherein R⁴ isC₁₋₄ alkyl.

Aspect 125. The compound of any one of aspects 115 to 122, wherein R⁴ issubstituted phenyl.

Aspect 126. The compound of aspect 115, wherein R² is methanediyl; R³ is—O—C(O)—R⁴; and R⁴ is substituted phenyl.

Aspect 127. The compound of aspect 126, wherein the one or moresubstituents is independently selected from halogen, C₁₋₃ alkyl, andC₁₋₃ alkoxy.

Aspect 128. The compound of aspect 126, wherein the substituted phenylis 2,6-substituted phenyl.

Aspect 129. The compound of aspect 128, wherein each of the substituentsis selected from C₁₋₃ alkyl and C₁₋₃ alkoxy.

Aspect 130. The compound of aspect 126, wherein the substituted phenylis 2,5,6-substituted phenyl.

Aspect 131. The compound of aspect 130, wherein each of the substituentsat the 2 and 6 positions is independently selected from C₁₋₃ alkyl andC₁₋₃ alkoxy; and the substituent at the 5 position is halogen.

Aspect 132. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ is independently selected from C₁₋₃ alkyl;    -   R² is a single bond; and    -   R³ is —CH═C(R⁴)₂, wherein each R⁴ is —C(O)—O—R⁸, or each R⁴        together with the carbon atom to which they are bonded from a        substituted heterocyclohexyl ring; and    -   each R⁸ is C₁₄ alkyl.

Aspect 133. The compound of aspect 132, each R⁴ is —C(O)—O—R⁸.

Aspect 134. The compound of aspect 132, each R⁴ is —C(O)—O—R⁸, or eachR⁴ together with the carbon atom to which they are bonded from asubstituted heterocyclohexyl ring.

Aspect 135. The compound of aspect 133, wherein in the substitutedheterocyclohexyl ring, the one or more heteroatoms is oxygen.

Aspect 136. The compound of any one of aspects 134 to 135, wherein inthe substituted heterocyclohexyl ring, the one or more substituents isindependently selected from C₁₋₃ alkyl and ═O.

Aspect 137. The compound of aspect 134, wherein the substitutedheterocycloalkyl ring is 2,2-dimethyl-5-yl-1,3-dioxane-4,6-dione.

Aspect 138. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ is independently selected from C₁₋₃ alkyl;    -   R² is selected from a single bond and methanediyl; and    -   R³ is substituted phenyl, wherein the one or more substituents        is independently selected from —CH₂—O—C(O)—R⁴ and —O—C(O)—R⁴,        wherein R⁴ is selected from C₁₋₁₀ alkyl and phenyl.

Aspect 139. The compound of aspect 138, wherein R² is a single bond.

Aspect 140. The compound of aspect 138, wherein R² is methanediyl;

Aspect 141. The compound of aspect 138, wherein R² is 2-substitutedphenyl.

Aspect 142. The compound of any one of aspects 138 to 141, wherein theone or more substituents is —CH₂—O—C(O)—R⁴.

Aspect 143. The compound of any one of aspects 138 to 141, wherein theone or more substituents is —O—C(O)—R⁴.

Aspect 144. The compound of any one of aspects 138 to 143, wherein R⁴ isC₁₋₁₀ alkyl.

Aspect 145. The compound of any one of aspects 138 to 143, wherein R⁴ isselected from methyl, ethyl, iso-propyl, pivalolyl, and phenyl.

Aspect 146. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ is independently selected from C₁₋₃ alkyl;    -   R² is selected from —C(R⁸)₂— and —CH₂—C(R⁸)₂—, wherein each R⁸        is independently selected from C₁₋₃ alkyl; and    -   R³ is selected from —C(O)—O—R⁴ and —O—C(O)—R⁴, wherein R⁴ is        selected from C₁₋₁₀ alkyl, C₁₋₁₀ heteroalkyl, substituted C₁₋₁₀        alkyl, substituted C₁₋₁₀ heteroalkyl, and        4(yl-methyl)-5-methyl-1,3-dioxol-2-one.

Aspect 147. The compound of aspect 146, wherein each R¹ is methyl.

Aspect 148. The compound of any one of aspects 146 to 147, wherein R² is—C(R⁸)₂—.

Aspect 149. The compound of any one of aspects 146 to 147, wherein R² is—CH₂—C(R⁸)₂—.

Aspect 150. The compound of any one of aspects 146 to 149, wherein eachR⁸ is methyl.

Aspect 151. The compound of any one of aspects 146 to 149, wherein eachR¹ is methyl; and each R⁸ is methyl.

Aspect 152. The compound of any one of aspects 146 to 151, wherein R³ is—C(O)—O—R⁴.

Aspect 153. The compound of any one of aspects 146 to 151, wherein R³ is—O—C(O)—R⁴.

Aspect 154. A compound of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each of R⁵, R⁶, and R⁷ is hydrogen;    -   A is a single bond;    -   each R¹ together with the carbon atom to which they are bonded        form a substituted C₅₋₆ heterocyclic ring;    -   R² is a single bond; and    -   R³ is C₁₋₃ alkyl.

Aspect 155. The compound of aspect 155, wherein in the substituted C₅₋₆heterocyclic ring, the one or more heteroatoms is oxygen; and the one ormore substituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 156. The compound of aspect 155, wherein each R¹ together withthe carbon atom to which they are bonded form atetrahydro-2H-pyran-2-one ring.

Aspect 157. The compound of aspect 155, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

A is a single bond;

each R¹ is independently selected from C₁₋₃ alkyl;

R² is selected from C₂₋₄ alkanediyl; and

R³ is substituted C₅₋₆ heterocycloalkyl, wherein the one or moreheteroatoms is independently selected from N and O; and the one or moresubstituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 158. The compound of aspect 157, wherein R⁴ has the structure ofFormula (6):

wherein R⁹ is selected from hydrogen, C₁₋₆ alkyl, C₄₋₆ cycloalkyl, C₁₋₆heteroalkyl, C₄₋₆ heterocycloalkyl, substituted C₁₋₆ alkyl, substitutedC₄₋₆ cycloalkyl, substituted C₁₋₆ heteroalkyl, and substituted C₄₋₆heterocycloalkyl.

Aspect 159. The compound of aspect 158, wherein R⁹ is selected fromhydrogen and C₁₋₆ alkyl.

Aspect 160. The compound of aspect 1, wherein the compound is selectedfrom:

-   ethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (3);-   benzyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (4);-   methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (10);-   isopropyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (11);-   hexyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (12);-   heptyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (13);-   tert-butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (14);-   2-methoxyethyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (15);-   oxetan-3-yl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (16);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate    (17);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopropanecarboxylate    (18);-   ethyl    1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate    (19);-   hexyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (36);-   heptyl    5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate    (37);-   (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl    ((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);-   S-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)    ethanethioate (53);-   propyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (57);-   butyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (58);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (59);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 161. A compound of Formula (4):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   each R¹ is independently selected from C₁₋₃ alkyl, or each R¹        together with the carbon atom to which they are bonded form a        C₃₋₆ cycloalkyl ring;    -   R² is a single bond; and    -   R³ is —C(O)—O—R⁴, wherein R⁴ is selected from C₁₋₁₀ alkyl, C₁₋₁₀        heteroalkyl, C₅₋₁₀ arylalkyl, C₃₋₆ heterocycloalkyl, and        substituted C₄₋₁₀ heterocycloalkylalkyl.

Aspect 162. The compound of aspect 161, wherein each R¹ is independentlyselected from C₁₋₃ alkyl.

Aspect 163. The compound of aspect 161, wherein each R¹ together withthe carbon atom to which they are bonded form a C₃₋₆ cycloalkyl ring.

Aspect 164. The compound of any one of aspects 161 to 163, wherein R⁴ isselected from C₁₋₇ alkyl, C₁₋₁₀ heteroalkyl wherein the one or moreheteroatoms is oxygen, —CH₂—C₄₋₆ cycloalkyl, —(CH₂)₂—C₄₋₆ cycloalkyl,C₃₋₆ heterocycloalkyl wherein the one or more heteroatoms is oxygen,—CH₂—C₃₋₆ substituted heterocycloalkyl, and —(CH₂)₂—C₃₋₆ substitutedheterocycloalkyl.

Aspect 165. The compound of aspect 163, wherein in the substituted C₃₋₆heterocycloalkyl the one or more heteroatoms is oxygen, and the one ormore substituents is independently selected from C₁₋₃ alkyl and ═O.

Aspect 166. The compound of aspect 161, wherein each R¹ is methyl, oreach R¹ together with the carbon atom to which they are bonded form acyclohexyl ring or a cyclopentyl ring.

Aspect 167. The compound of any one of aspects 161 to 166, wherein R⁴ isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, n-hexyl,n-heptyl, —CH₂—CH₂—O—CH₃, benzyl, 3-oxetanyl, andmethyl-5-methyl-1,3-dioxol-2-one.

Aspect 168. The compound of aspect 161, wherein,

each of R⁵, R⁶, and R⁷ is hydrogen;

A is a single bond;

R² is a single bond; and

R³ is —C(O)—O—R⁴, wherein R⁴ is C₁₋₁₀ alkyl.

Aspect 169. A compound of Formula (4) is selected from:

-   ethyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (20);-   2-methoxyethyl    2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (21);-   4-((1R,2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (22);-   4-((1R,2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (23);-   4-((1R,2S,5R)-6-((((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (24);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (25);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 170. A compound of Formula (4) is selected from:

-   ethyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (20);-   4-((1R,2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (22);-   4-((1R,2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium    2,2,2-trifluoroacetate (23);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate    (25);    -   a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 171. A compound of Formula (5) is selected from:

-   ethyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (27);-   2-methoxyethyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    (28);-   (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    TFA salt (29);-   hexyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    TFA salt (30);-   heptyl    3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate    TFA salt (31);-   ethyl    1-((((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate    TFA salt (32);

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

Aspect 172. A pharmaceutical composition comprising the compound of anyone of aspects 76 to 171 and a pharmaceutically acceptable vehicle.

Aspect 173. The pharmaceutical composition of aspect 172, furthercomprising an antibiotic.

Aspect 174. The pharmaceutical composition of aspect 173, wherein theantibiotic comprises a β-lactam antibiotic.

Aspect 175. The pharmaceutical composition of any one of aspects 172 to174, wherein the pharmaceutical composition comprises an oral dosageformulation.

Aspect 176. The pharmaceutical composition of any one of aspects 172 to175, wherein the pharmaceutical composition comprises an oral dosageform.

Aspect 177. The pharmaceutical composition of any one of aspects 172 to176, comprising an amount of the compound of any one of aspects 76 to171 effective for treating a bacterial infection in a patient.

Aspect 178. A method of treating a bacterial infection in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the compound of any one of aspects76 to 171.

Aspect 179. The method of aspect 178, wherein administering comprisesorally administering.

Aspect 180. The method of any one of aspects 178 to 179, whereinadministering comprises administering an oral dosage form.

Aspect 181. The method of any one of aspects 178 to 180, furthercomprising administering an antibiotic to the patient.

Aspect 182. The method of any one of aspects 178 to 181, wherein theantibiotic comprises a β-lactam antibiotic.

Aspect 183. A method of treating a bacterial infection in a patientcomprising administering to a patient in need of such treatment atherapeutically effective amount of the pharmaceutical composition ofany one of aspects 172 to 177.

Aspect 184. The method of aspect 183, wherein administering comprisesorally administering.

Aspect 185. The method of any one of aspects 183 to 184, whereinadministering comprises administering an oral dosage form.

Aspect 186. The method of any one of aspects 183 to 185, furthercomprising administering an antibiotic to the patient.

Aspect 187. The method of aspect 184, wherein the antibiotic comprises aβ-lactam antibiotic.

Aspect 188. A method of inhibiting a β-lactamase in a patient comprisingadministering to the patient an effective amount of the compound of anyone of aspects 76 to 171.

Aspect 189. The method of aspect 188, wherein administering comprisesorally administering.

Aspect 190. The of any one of aspects 188 to 189, wherein administeringcomprises administering an oral dosage form.

Aspect 191 A method of inhibiting a β-lactamase in a patient comprisingadministering to the patient an effective amount of the pharmaceuticalcomposition of any one of aspects 172 to 177.

Aspect 192. The method of aspect 191, wherein administering comprisesorally administering.

Aspect 193. The method of any one of aspects 191 to 192, whereinadministering comprises administering an oral dosage form.

Aspect 194. A method of preparing a sulfate monoester analog of a cyclichydroxamic acid comprising reacting the cyclic hydroxamic acid with achlorosulfonate ester in the presence of a base to provide sulfatemonoester analog.

Aspect 195. The method of aspect 194, wherein the cyclic hydroxamic acidhas the structure of Formula (82) and the chlorosulfate ester has thestructure of Formula (83):

where,

R is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈ cycloalkyl, C₅₋₈heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀ heterocycloalkylalkyl,C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀ arylalkyl, C₅₋₁₀ heteroarylalkyl,substituted C₁₋₈ alkyl, substituted C₁₋₈ heteroalkyl, substituted C₅₋₈cycloalkyl, substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl, substitutedC₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted C₇₋₁₀ arylalkyl, andsubstituted C₅₋₁₀ heteroarylalkyl;

n is an integer from 1 to 6;

each A is independently selected from —(CH₂)—, —(CHR)—, —(CR₂)—, —NH—,—NR—, 0, and S, where R is independently elected from hydrogen, C₁₋₈alkyl, C₁₋₈ heteroalkyl, C₅₋₈ cycloalkyl, C₅₋₈ heterocycloalkyl, C₅-C₁₀cycloalkylalkyl, C₅₋₁₀ heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈heteroaryl, C₇₋₁₀ arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈alkyl, substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀ cycloalkylalkyl,substituted C₅₋₁₀ heterocycloalkylalkyl, substituted C₆₋₈ aryl,substituted C₅₋₈ heteroaryl, substituted C₇₋₁₀ arylalkyl, andsubstituted C₅₋₁₀ heteroarylalkyl; or one A is bonded to another Athrough a group -L-, where L is selected from C₁₋₈ alkyl, C₁₋₈heteroalkyl, substituted C₁₋₈ alkyl, and substituted C₁₋₈ heteroalkyl.

Aspect 196. The method of aspect 194, wherein the sulfate monoesteranalog comprises a compound of Formula (80a) and the cyclic hydroxamicacid comprises a compound of Formula (80b):

wherein,

-   -   R is selected from C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ to heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅-C₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl;    -   R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂        cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂        heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈        cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆        heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted        C₆₋₁₂ heterocycloalkylalkyl;    -   R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂        cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂        heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈        cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆        heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted        C₆₋₁₂ heterocycloalkylalkyl; and    -   A is a single bond (—) and R⁷ is hydrogen, or A is a double bond        (═) and R⁷ is C₁₋₃ alkyl.

Aspect 197. The method of any one of aspects 194 to 196, wherein thechlorosulfonate monoester comprises a chlorosulfonate neopentyl ester.

Aspect 198. The method of any one of aspects 194 to 197, wherein thechlorosulfonate neopentyl ester has the structure of Formula (81):

wherein,

-   -   each R¹ is independently selected from C₁₋₆ alkyl, or each R¹        and the geminal carbon atom to which they are bonded forms a        C₃₋₆ cycloalkyl ring, a C₃₋₆ heterocycloalkyl ring, a        substituted C₃₋₆ cycloalkyl ring, or a substituted C₃₋₆        heterocycloalkyl ring;    -   R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆        heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆        heterocycloalkanediyl, C₆ arenediyl, C₅₋₆ heteroarenediyl,        substituted C₁₋₆ alkanediyl, substituted C₁₋₆ heteroalkanediyl,        substituted C₅₋₆ cycloalkanediyl, substituted C₅₋₆        heterocycloalkanediyl, substituted C₆ arenediyl, and substituted        C₅₋₆ heteroarenediyl; and    -   R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴,        —NH—C(O)—R⁴, —O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴,        —C(O)—O—R⁴, —C(O)—S—R⁴, —C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴,        —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴, —NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆        heterocycloalkyl, C₅₋₆ heteroaryl, substituted C₅₋₆ cycloalkyl,        substituted C₅₋₆ heterocycloalkyl, substituted C₅₋₆ aryl,        substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂, wherein,    -   R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈        cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₅₋₁₀        heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀        arylalkyl, C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl,        substituted C₁₋₈ heteroalkyl, substituted C₅₋₈ cycloalkyl,        substituted C₅₋₈ heterocycloalkyl, substituted C₅₋₁₀        cycloalkylalkyl, substituted C₅₋₁₀ heterocycloalkylalkyl,        substituted C₆₋₈ aryl, substituted C₅₋₈ heteroaryl, substituted        C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀ heteroarylalkyl.

Aspect 199. The method of any one of aspects 194 to 198, wherein thechlorosulfate monoester is prepared by reacting an alcohol with sulfurylchloride.

Aspect 200. The method of aspect 199, wherein the alcohol comprises aneopentyl alcohol.

Aspect 201. The method of aspect 194, wherein the sulfate monoesteranalog has the structure of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

each R¹ is independently selected from C₁₋₆ alkyl, or each R¹ and thegeminal carbon atom to which they are bonded forms a C₃₋₆ cycloalkylring, a C₃₋₆ heterocycloalkyl ring, a substituted C₃₋₆ cycloalkyl ring,or a substituted C₃₋₆ heterocycloalkyl ring;

R² is selected from a single bond, C₁₋₆ alkanediyl, C₁₋₆heteroalkanediyl, C₅₋₆ cycloalkanediyl, C₅₋₆ heterocycloalkanediyl, C₆arenediyl, C₅₋₆ heteroarenediyl, substituted C₁₋₆ alkanediyl,substituted C₁₋₆ heteroalkanediyl, substituted C₅₋₆ cycloalkanediyl,substituted C₅₋₆ heterocycloalkanediyl, substituted C₆ arenediyl, andsubstituted C₅₋₆ heteroarenediyl;

R³ is selected from C₁₋₆ alkyl, —O—C(O)—R⁴, —S—C(O)—R⁴, —NH—C(O)—R⁴,—O—C(O)—O—R⁴, —S—C(O)—O—R⁴, —NH—C(O)—O—R⁴, —C(O)—O—R⁴, —(O)—S—R⁴,—C(O)—NH—R⁴, —O—C(O)—O—R⁴, —O—C(O)—S—R⁴, —O—C(O)—NH—R⁴, —S—S—R⁴, —S—R⁴,—NH—R⁴, —CH(—NH₂)(—R⁴), C₅₋₆ heterocycloalkyl, C₅₋₆ heteroaryl,substituted C₅₋₆ cycloalkyl, substituted C₅₋₆ heterocycloalkyl,substituted C₅₋₆ aryl, substituted C₅₋₆ heteroaryl, and —CH═C(R⁴)₂,wherein,

R⁴ is selected from hydrogen, C₁₋₈ alkyl, C₁₋₈ heteroalkyl, C₅₋₈cycloalkyl, C₅₋₈ heterocycloalkyl, C₅₋₁₀ cycloalkylalkyl, C₁₋₁₀heterocycloalkylalkyl, C₆₋₈ aryl, C₅₋₈ heteroaryl, C₇₋₁₀ arylalkyl,C₅₋₁₀ heteroarylalkyl, substituted C₁₋₈ alkyl, substituted C₁₋₈heteroalkyl, substituted C₅₋₈ cycloalkyl, substituted C₅₋₈heterocycloalkyl, substituted C₅-C₁₀ cycloalkylalkyl, substituted C₅₋₁₀heterocycloalkylalkyl, substituted C₆₋₈ aryl, substituted C₅₋₈heteroaryl, substituted C₇₋₁₀ arylalkyl, and substituted C₅₋₁₀heteroarylalkyl;

R⁵ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl;

R⁶ is selected from hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, C₆₋₁₂cycloalkylalkyl, C₂₋₆ heteroalkyl, C₅₋₈ heterocycloalkyl, C₆₋₁₂heterocycloalkylalkyl, substituted C₁₋₆ alkyl, substituted C₅₋₈cycloalkyl, substituted C₆₋₁₂ cycloalkylalkyl, substituted C₂₋₆heteroalkyl, substituted C₅₋₈ heterocycloalkyl, and substituted C₆₋₁₂heterocycloalkylalkyl; and

A is a single bond (—) and R⁷ is hydrogen, or A is a double bond (═) andR⁷ is C₁₋₃ alkyl.

EXAMPLES

The following examples describe in detail the synthesis of compounds ofFormula (1), characterization of compounds of Formula (1), and uses ofcompounds of Formula (1). It will be apparent to those skilled in theart that many modifications, both to materials and methods, may bepracticed without departing from the scope of the disclosure.

Example 1 Synthesis of(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1)

Reference is made to International Application Publication No. WO2012/086241 and International Application No. PCT/2012/016553, togetherwith related procedures from the patent literature. A stirred mixture of(1R,2S,5R)-6-(benzyloxy-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(550 mg, 2.0 mmol), palladium on carbon (10% by weight; 340 mg, 0.3mmol) and MeOH (18 mL) was hydrogenated under 1 atm (balloon) untilanalysis by thin-layer chromatography (TLC) indicated completion of thereaction (approximately, 30 min; reaction monitored by TLC usingMeOH/CH₂Cl₂ 5:95 as eluent). The mixture was filtered through a pad ofCelite® and the pad was rinsed thoroughly with MeOH (ca. 20 mL). Thefiltrate was concentrated under vacuum (water bath temperature notexceeding 25° C.) to give the product as a clear and colorless oil. Theoil was dried under vacuum for 1 h, and the residue was used immediatelyin the next step without further purification. Yield assumedquantitative. LC-MS: m/z=186.0 [M+H]⁺.

Example 2 Synthesis of3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropylbenzoate (2)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl benzoate (2a)

Benzoyl chloride (4.0 mL, 34.5 mmol) was added dropwise to a stirredsolution of 2,2-dimethylpropane-1,3-diol (10.8 g, 103.4 mmol), pyridine(5.8 mL, 71.6 mmol) and N,N-4-dimethylaminopyridine (840 mg, 6.9 mmol)in dichloromethane (207 mL) at ca. 0° C. The mixture was stirredovernight with gradual warming to room temperature, quenched by additionof 1N HCl (100 mL) at 0° C. and extracted twice with dichloromethane.The combined organic extracts were washed with saturated aqueous NaHCO₃(100 mL), brine (100 mL), dried (Na₂SO₄), filtered and the solventconcentrated under vacuum to leave a crude residue. The residue wassplit into two batches and purified by column chromatography on silicagel using EtOAc/hexanes (0:1 to 1:4) as eluent to give the product (5.95g, 99%) as a colorless oil (note: oil dried under vacuum for 2 days).LC-MS: m/z=209.0 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): 8.05 (m, 2H), 7.58 (m,1H), 7.45 (m, 2H), 4.19 (s, 2H), 3.38 (d, J=6.3 Hz, 2H), 2.29 (t, J=6.3Hz, 1H), 1.02 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl benzoate(2b)

Reference is made to J. Am. Chem. Soc. 2006, 128, 1605-1610. A solutionof distilled sulfuryl chloride (1.2 mL, 15.8 mmol) in Et₂O (15 mL) wascooled to −78° C. under an atmosphere of argon. A solution of3-hydroxy-2,2-dimethylpropyl benzoate (2a) (3.0 g, 14.4 mmol) andpyridine (1.2 mL, 14.4 mmol) in Et₂O (3.0 mL) was then added dropwiseover 1 h via a syringe. The syringe was rinsed with Et₂O (3×1 mL), eachrinse being added to the reaction mixture. The acetone/CO₂ bath wasremoved, and the mixture allowed to warm to room temperature, thenstirred at room temperature for 4 h. TLC analysis (EtOAc/hexanes; 3:7)did not indicate complete reaction, so re-cooled to −78° C. and addedmore SO₂Cl₂ (0.1 mL), then allowed to warm to room temperature, andstirred for an additional 2 h. The mixture was filtered and the filtratewas concentrated under vacuum to give the product (3.97 g, 89%) as anoil. ¹H NMR (300 MHz, CDCl₃): 8.03 (m, 2H), 7.61-7.57 (m, 1H), 7.49-7.44(m, 2H), 4.41 (s, 2H), 4.18 (s, 2H), 1.16 (s, 6H).

Step 3: Synthesis of3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropylbenzoate (2)

Reference is made to J. Am. Chem. Soc. 2006, 128, 1605-1610.(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (370 mg, 2.0 mmol) was dissolved in THF (7.0 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (3.0 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A solutionof NaHMDS in THF (1M; 2.2 mL, 2.2 mmol) was added dropwise, and themixture was stirred at −78° C. for 10 min.3-((Chlorosulfonyl)oxy)-2,2-dimethylpropyl benzoate (2b) (674 mg, 2.2mmol) was then added quickly to the reaction mixture. After 10 min at−78° C., the reaction mixture was allowed to warm to room temperatureand stirred at room temperature until judged complete by LC-MS and TLCanalysis. EtOAc (20 mL) and saturated aqueous NaHCO₃ (20 mL) were added,and the organic and aqueous layers were partitioned. The organic layerwas washed with water (3×20 mL), brine (20 mL), dried (Na₂SO₄), andconcentrated under vacuum to leave a crude residue. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (1:9to 1:0) as eluent to give the product (400 mg, 43%) as a solid. Afterpurification by column chromatography, the product appeared to degradeto a certain extent after drying the compound under vacuum over theweekend—one degradant was presumably avibactam by LC-MS, m/z=529.0[2M−H]⁻. A portion of the material was subsequently re-purified bycolumn chromatography on silica gel using the eluent system detailedabove. The product was then stored at −20° C. immediately afterisolation. LC-MS: m/z=456.2 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d,J=6.9 Hz, 2H), 7.59-7.54 (m, 1H), 7.47-7.42 (m, 2H), 6.49 (s, 1H), 5.91(s, 1H), 4.69 (d, J=9.3 Hz, 1H), 4.44 (d, J=9.3 Hz, 1H), 4.16-4.14 (m,3H), 4.00 (d, J=7.5 Hz, 1H), 3.24-3.20 (m, 1H), 2.96 (d, J=11.7 Hz, 1H),2.43-2.36 (m, 1H), 2.16-2.09 (m, 1H), 1.97-1.80 (m, 2H), 1.13 (s, 3H),1.12 (s, 3H). ¹³C NMR (300 MHz, CDCl₃): δ 171.1, 167.1, 166.4, 133.3,130.0, 129.8, 128.6, 80.7, 69.1, 62.0, 60.2, 47.1, 35.7, 21.5, 20.8,17.6.

Example 3 Synthesis of ethyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(3)

Step 1: Synthesis of ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a)

A solution of distilled sulfuryl chloride (0.55 mL, 7.5 mmol) in Et₂O(10 mL) was cooled to −78° C. under an atmosphere of argon. A solutionof ethyl 3-hydroxy-2,2-dimethylpropanoate (2a) (1.0 g, 6.8 mmol) andpyridine (0.55 mL, 6.8 mmol) in Et₂O (1.0 mL) was then added dropwiseover 1 h via a syringe. The syringe was rinsed with Et₂O (3×1 mL), eachrinse being added to the reaction mixture. The acetone/CO₂ bath wasremoved, and the mixture was allowed to warm to room temperature, thenstirred at room temperature for 4 h. TLC analysis (EtOAc/hexanes; 3:7)did not indicate that the reaction was complete. The mixture wasre-cooled to −78° C. and more SO₂Cl₂ (0.11 mL) was added, and themixture allowed to warm to room temperature and stirred for anadditional 2 h. The mixture was filtered and the filtrate wasconcentrated under vacuum to give the product (yield assumedquantitative). ¹H NMR (300 MHz, CDCl₃): δ 4.50 (s, 2H), 4.19 (q, J=6.9Hz, 2H), 1.31 (s, 6H), 1.28 (t, J=6.9 Hz, 3H).

Step 2: Synthesis of ethyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(3)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (370 mg, 2.0 mmol) was dissolved in THF (7.0 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (3.0 mL) and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A solutionof NaHMDS in THF (1M; 2.2 mL, 2.2 mmol) was added dropwise, and themixture was stirred at −78° C. for 10 min. A solution of ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) (538 mg, 2.2 mmol)in THF (1 mL) was then added quickly to the reaction mixture viasyringe. The syringe was rinsed with THF (3×0.5 mL), each rinse beingadded to the reaction mixture. After 10 min at −78° C., the reactionmixture was allowed to warm to room temperature and stirred at roomtemperature until judged complete by LC-MS and TLC analysis (ca. 2 h).EtOAc (20 mL) and saturated aqueous NaHCO₃ (20 mL) were added and theorganic and aqueous layers were partitioned. The organic layer waswashed with saturated NaHCO₃ (20 mL), water (3×20 mL), brine (20 mL),dried (Na₂SO₄) and concentrated under vacuum to leave a crude residue.The residue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:9 to 1:0) as eluent to give the product (318 mg, 39%)as a solid. LC-MS: m/z=394.1 [M+H]⁺. ¹H NMR (CDCl₃, 300 MHz): δ 6.50 (s,1H), 5.78 (s, 1H), 4.71 (d, J=8.7 Hz, 1H), 4.59 (d, J=8.7 Hz, 1H),4.22-4.12 (m, 3H), 4.05 (d, J=6.9 Hz, 1H), 3.34-3.30 (m, 1H), 3.01 (d,J=12.3 Hz, 1H), 2.46-2.40 (m, 1H), 2.18-2.12 (m, 1H), 2.00-1.79 (m, 2H),1.28-1.24 (m, 9H). ¹³C NMR (300 MHz, CDCl₃): δ 174.2, 171.2, 167.1,80.5, 61.9, 61.4, 60.2, 47.2, 42.8, 22.2, 21.7, 20.8, 17.5, 14.2.

Example 4 Synthesis of benzyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(4)

Step 1: Synthesis of benzyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (4a)

A solution of distilled sulfuryl chloride (0.77 mL, 10.6 mmol) in Et₂O(10 mL) was cooled to −78° C. under an atmosphere of argon. A solutionof ethyl 3-hydroxy-2,2-dimethylpropanoate (2a) (Sigma-Aldrich; 2.0 g,9.6 mmol) and pyridine (0.85 mL, 10.6 mmol) in Et₂O (2.0 mL) was thenadded dropwise over 1 h via a syringe. The syringe was rinsed with Et₂Owith each rinse being added to the reaction mixture. The acetone/CO₂bath was removed and the mixture allowed to warm to room temperature,then stirred at room temperature for 30 min. TLC analysis(EtOAc/hexanes; 3:7) did not indicate complete reaction, so re-cooled to−78° C. and added more SO₂Cl₂ (0.07 mL), then allowed to warm to roomtemperature and stirred for an additional 1 h. Et₂O (5 mL) was added andthe mixture stirred for a few min, then filtered and the filtrateconcentrated under vacuum to give the product (2.19 g, 75%). ¹H NMR (300MHz, CDCl₃): δ 7.41-7.32 (m, 4H), 5.18 (s, 2H), 4.52 (s, 2H), 1.34 (s,6H).

Step 2: Synthesis of benzyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(4)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (370 mg, 2.0 mmol) was dissolved in THF (7.0 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (2.0 mL) was added, and theresulting solution was cooled to −78° C. under an atmosphere of argon. Asolution of NaHMDS in THF (1M; 2.2 mL, 2.2 mmol) was added dropwise, andthe mixture was stirred at −78° C. for 10 min. A solution of ethylbenzyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (4a) (674 mg, 2.2mmol) in THF (1 mL) was then added quickly to the reaction mixture viasyringe. The syringe was rinsed with THF (3×0.5 mL), each rinse beingadded to the reaction mixture. After 10 min at −78° C., the reactionmixture was allowed to warm to room temperature and stirred at roomtemperature until judged complete by LC-MS and TLC analysis. EtOAc (20mL) and saturated aqueous NaHCO₃ (20 mL) were added, and the organic andaqueous layers were partitioned. The organic layer was washed withsaturated NaHCO₃ (20 mL), water (3×20 mL), brine (20 mL), dried (Na₂SO₄)and concentrated under vacuum to leave a crude residue. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (1:9to 1:0) as eluent to give the product (244 mg, 26%) as a solid. LC-MS:m/z=456.2 [M+H]⁺. ¹H NMR (CDCl₃, 300 MHz): δ 7.39-7.28 (m, 4H), 6.49 (s,1H), 5.84 (s, 1H), 5.20-5.11 (m, 2H), 4.74 (d, J=9.0 Hz, 1H), 4.61 (d,J=9.0 Hz, 1H), 4.15-4.14 (m, 1H), 4.04 (d, J=6.9 Hz, 1H), 3.29-3.25 (m,1H), 2.99 (d, J=11.7 Hz, 1H), 2.45-2.38 (m, 1H), 2.17-2.10 (m, 1H),1.99-1.78 (m, 2H), 1.30 (s, 3H), 1.29 (s, 3H). ¹³C NMR (CDCl₃, 75 MHz):δ 174.1, 171.1, 167.1, 135.7, 128.7, 128.4, 128.0, 80.3, 67.0, 62.0,60.2, 47.2, 43.0, 22.2, 21.7, 20.8, 17.5.

Example 5 Synthesis of(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl phenylsulfate (5)

Step 1: Synthesis of phenyl sulfochloridate (5a)

Reference is made to J. Am. Chem. Soc. 2013, 135, 10638-10641. Asolution of distilled sulfuryl chloride (2.6 mL, 35.1 mmol) in Et₂O (30mL) was cooled to −78° C. under an atmosphere of argon. A solution ofphenol (3.0 g, 31.9 mmol) in Et₂O (3.0 mL) and pyridine (2.6 mL, 31.9mmol) were then added concurrently, but from different syringes,dropwise over 1 h. The syringes were each rinsed with Et₂O and eachrinse was added to the reaction mixture. The mixture was allowed to warmto room temperature slowly, and stirred at room temperature overnight.The mixture was filtered, and the filtrate concentrated under vacuum togive the product (4.65 g), contaminated with other products and phenolstarting material. The phenyl sulfochloridate product was not purifiedfurther and was used directly in the next step.

Step 2: Synthesis of(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl phenylsulfate (5)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (370 mg, 2.0 mmol) was dissolved in THF (7.0 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (2.0 mL) and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A solutionof NaHMDS in THF (1M; 2.2 mL, 2.2 mmol) was added dropwise and themixture was stirred at −78° C. for 10 min. Neat phenyl sulfochloridate(5a) (423 mg, 2.2 mmol) was then added quickly to the reaction mixturevia syringe. The syringe was rinsed with THF (3×0.5 mL), each rinsebeing added to the reaction mixture. After 10 min at −78° C., thereaction mixture was allowed to warm to room temperature and stirred atroom temperature until judged complete by LC-MS and TLC analysis (ca. 1h). EtOAc (20 mL) and saturated aqueous NaHCO₃ (20 mL) were added, andthe organic and aqueous layers were partitioned. The organic layer waswashed with saturated NaHCO₃ (20 mL), water (3×20 mL), brine (20 mL),dried (Na₂SO₄), and concentrated under vacuum to leave a crude residue.The residue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:9 to 1:0) as eluent to give the product (126 mg, 18%)as a solid. LC-MS: m/z=342.2 [M+H]⁺. 1H NMR (300 MHz, CDCl3): δ7.54-7.51 (m, 2H), 7.47-7.42 (m, 2H), 7.39-7.33 (m, 1H), 6.53 (s, 1H),5.88 (s, 1H), 4.24 (fd, J=2.4 Hz, 1H), 4.09 (d, J=6.9 Hz, 1H), 3.34 (d,J=11.7 Hz, 1H), 3.05 (d, J=12.3 Hz, 1H), 2.46-2.39 (m, 1H), 2.19-2.11(m, 1H), 2.02-1.81 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 171.2, 166.8,150.9, 130.2, 128.1, 121.3, 62.1, 60.6, 47.0, 20.8, 17.6.

Example 6 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutylbenzoate (6)

Step 1: Synthesis of 2,2-dimethylbutane-1,4-diol (6a)

A solution of 2,2-dimethylsuccinic acid (10.0 g, 68.4 mmol) in THF (150mL) was added dropwise to a suspension of lithium aluminum hydride (8.3g, 219.0 mmol) in THF (80 mL) at 0° C. (ice bath). The mixture waswarmed to room temperature over 20 min and then heated at reflux for 1.5h. Upon completion (reaction monitored by TLC using MeOH/CH₂Cl₂ 5:95 aseluent) the reaction was quenched very carefully and dropwise by theaddition of water (10 mL), 3 M NaOH (15 mL), and water (20 mL). Themixture was stirred at room temperature for 20 min, and the solidsfiltered over a pad of Celite®. The filter cake was rinsed thoroughlywith THF. The filtrate was concentrated under vacuum giving a mixture ofthe title compound and unidentified by-products as a crude oil. The oilwas purified by column chromatography on silica gel using MeOH/CH₂Cl₂(0:1 to 1:9) as eluent to afford the product (4.649 g, 57%) as an oil.¹H-NMR (300 MHz, CDCl₃): δ 4.11 (s, 2H), 3.66 (t, J=5.9 Hz, 2H), 3.30(s, 2H), 1.52 (t, J=5.6 Hz, 2H), 0.89 (s, 6H).

Step 2: Synthesis of 4-hydroxy-3,3-dimethylbutyl benzoate (6b)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (6a) (0.30 g, 2.5mmol) in anhydrous dichloromethane (9 mL) was added benzoyl chloride(0.30 mL, 2.5 mmol), Et₃N (0.71 mL, 5.1 mmol), and a catalytic amount ofN,N-4-dimethylaminopyridine at 0° C. (ice bath). The mixture wasgradually warmed to room temperature and stirred overnight. After thestarting material was completely consumed (reaction monitored by TLCusing EtOAc/hexanes 2:8 as eluent), the reaction was quenched by theaddition of 1N HCl (20 mL) at 0° C. (ice bath), and the mixture wasextracted twice with dichloromethane. The combined organic layers werewashed with saturated aqueous NaHCO₃, brine, dried (Na₂SO₄), filteredand the solvent concentrated to yield a mixture, of at least twoproducts, as a clear and colorless oil. The oil was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 4:6) as eluentto give the product (0.29 g, 51%) as an oil (which was dried under highvacuum for 2 d). ¹H-NMR (300 MHz, CDCl₃): δ 8.04-8.01 (m, 2H), 7.58-7.53(m, 1H), 7.46-7.41 (m, 2H), 4.41 (t, J=7.4 Hz, 2H), 3.41 (s, 2H), 1.78(t, J=7.4 Hz, 2H), 1.70 (s, 1H), 0.99 (s, 6H).

Step 3: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl benzoate(6c)

A solution of freshly distilled sulfuryl chloride (0.11 mL, 1.5 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof 4-hydroxy-3,3-dimethylbutyl benzoate (6b) (0.28 g, 1.3 mmol) andpyridine (0.10 ml, 1.3 mmol) in Et₂O (2 mL) was added dropwise (over 1h) to the cooled solution. The mixture was warmed to room temperatureand stirred for 30 min (reaction was monitored by TLC usingEtOAc/hexanes 2:8 as eluent). The mixture was re-cooled to −78° C. andsulfuryl chloride (0.02 mL) was added. The mixture was allowed to warmto room temperature, and stirred for 30 min. Et₂O (5 mL) was added andthe mixture stirred for a few minutes. The mixture was filtered and thefiltrate concentrated under vacuum to give the product (0.305 g, 75%).¹H-NMR (300 MHz, CDCl₃): δ 8.03 (d, J=8.1 Hz, 2H), 7.60-7.54 (m, 1H),7.47-7.42 (m, 2H), 4.44-4.38 (m, 2H), 4.29 (s, 2H), 1.89-1.85 (m, 2H),1.13 (s, 6H).

Step 4: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutylbenzoate (6)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (176 mg, 1.0 mmol) was dissolved in THF (4 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (1 mL) and the resultingsolution was cooled to −78° C. under an atmosphere of Argon. NaHMDS (1.0M in THF; 1.05 mL, 1.05 mmol) was added dropwise to the cooled solutionand the mixture was stirred at −78° C. for 10 min.4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl benzoate (6c) (305 mg, 1.0mmol) in THF (0.5 mL) was added quickly to the mixture. The syringe wasrinsed with THF (3×0.5 mL) and this was also added to the mixture. After10 min, the mixture was warmed to room temperature and stirred untiljudged complete by TLC analysis. EtOAc (10 mL) and saturated aqueousNaHCO₃ (10 mL) were added to the mixture and the organic and aqueouslayers were partitioned. The organic layer was washed with saturatedaqueous NaHCO₃ (10 mL), water (6×10 mL), brine (10 mL), dried (Na₂SO₄),filtered and concentrated under vacuum. Purification by columnchromatography on silica gel using EtOAc/hexanes (1:9 to 1:0) as eluentgave the product (6) (215 mg, 18%) as a solid. LC-MS: 470.2 [M+H]⁺.1H-NMR (300 MHz, CDCl3): δ 8.04-8.01 (m, 2H), 7.58-7.53 (m, 1H),7.46-7.41 (m, 2H), 6.48 (s, 1H), 5.80 (s, 1H), 4.60 (d, J=9.3 Hz, 1H),4.40 (t, J=6.9 Hz, 2H), 4.29 (d, J=9.3 Hz, 1H), 4.17-4.16 (m, 1H), 4.02(d, J=7.8 Hz, 1H), 3.34-3.30 (m, 1H), 3.00 (d, J=12.3 Hz, 1H), 2.45-2.35(m, 1H), 2.17-2.11 (m, 1H), 1.98-1.78 (m, 4H), 1.10 (s, 6H). ¹³C-NMR (75MHz, CDCl₃): δ 171.1, 167.1, 166.6, 133.1, 130.2, 129.7, 128.5, 83.7,61.9, 61.5, 60.2, 47.2, 36.9, 34.1, 24.1, 23.8, 20.8, 17.5.

Example 7 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutylpropionate (7)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl propionate (7a)

A solution of propionyl chloride (0.74 mL, 8.5 mmol) in anhydrousdichloromethane (5 mL) was added to a stirred solution of2,2-dimethylbutane-1,4-diol (6a) (1.00 g, 8.5 mmol), Et₃N (2.4 mL, 16.9mmol), and 4-N,N-dimethylaminopyridine (52 mg) in anhydrousdichloromethane (20 mL) at −78° C. under an atmosphere of argon. Themixture was stirred for 10 min and then allowed to warm to roomtemperature, stirred at room temperature for 1 h, then re-cooled to −78°C., and allowed to warm to room temperature slowly by allowing themixture to stay in the cold bath and letting the dry ice sublime(recommended to allow warming to room temperature from −78° C. afteraddition of all the reagents). After the starting material wascompletely consumed (TLC 50% EtOAc/hexanes), the reaction was quenchedby the addition of 0.5 N HCl (10 mL) at 0° C. The organic and aqueouslayers were partitioned, and the aqueous layer was extracted withdichloromethane (2×20 mL). The combined organic layers were washed withsaturated aqueous NaHCO₃ (20 mL), brine (20 mL), then dried (Na₂SO₄),filtered and the solvent concentrated under vacuum to leave a crude oil.The oil was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 4:1) as eluent to give the product (7a) (463 mg,22%) as an oil, contaminated with significant EtOAc solvent residues.¹H-NMR (300 MHz, CDCl₃): δ 4.14 (t, J=7.4 Hz, 2H), 3.32 (s, 2H), 2.30(q, J=7.6 Hz, 2H), 1.88 (s, 1H), 1.61 (t, J=7.7 Hz, 2H), 1.13 (t, J=7.5Hz, 3H), 0.91 (fd, J=1.2 Hz, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutylpropionate (7b)

A solution of freshly distilled sulfuryl chloride (0.15 mL, 2.0 mmol) inEt₂O (3.5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 4-hydroxy-3,3-dimethylbutyl propionate (7a) (73% purity, theremainder being EtOAc; 441 mg, 1.8 mmol) and pyridine (0.15 mL, 1.8mmol) in Et₂O (2.5 mL) was added dropwise over 1 h to the cooledsolution. The mixture was allowed to warm to room temperature and wasstirred for 30 min (monitored by TLC, 30% EtOAc/hexanes), re-cooled to−78° C. and sulfuryl chloride (0.03 mL) and pyridine (0.03 mL) wasadded, warmed to room temperature, and stirred for 30 min. Again, themixture was re-cooled to −78° C. and another portion of sulfurylchloride (0.15 mL) was added. The mixture was allowed to warm to roomtemperature, and stirred for 30 min. Et₂O (5 mL) was added and themixture stirred for a few min. The mixture was filtered and the filtratewas concentrated under vacuum to give the product (7b) (401 mg, 79%).¹H-NMR: (300 MHz, CDCl₃): 4.22 (s, 2H), 4.14 (t, J=6.8 Hz, 2H), 2.30 (q,J=7.6 Hz, 2H), 1.70 (t, J=6.8 Hz, 2H), 1.11 (t, J=7.7 Hz, 3H), 1.05 (s,6H).

Step 3: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutylpropionate (7)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (185 mg, 1.0 mmol) was dissolved in THF (4 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (1 mL) under an atmosphere ofargon. The resulting solution was cooled to −78° C. NaHMDS (1.0 M inTHF; 1.1 mL, 1.1 mmol) was added dropwise to the cooled solution and themixture stirred for 10 min. 4-((chlorosulfonyl)oxy)-3,3-dimethylbutylpropionate (7b) (272 mg, 1.0 mmol) in THF (1 mL) was added quickly tothe reaction mixture. The syringe was rinsed with THF (3×0.5 mL) andthis was also added to the mixture. Further THF (3 mL) was added to themixture to allow efficient stirring of the reaction. After 10 min, themixture was allowed to warm to room temperature. Upon completion (1 h;TLC, 70% EtOAc/hexanes), EtOAc (10 mL) and saturated aqueous NaHCO₃ (10mL) were added to the mixture. The aqueous and organic layers werepartitioned, and the organic layer was washed with saturated aqueousNaHCO₃ (10 mL), water (6×10 mL), brine (10 mL), then dried (Na₂SO₄),filtered and the solvent concentrated under vacuum to leave a cruderesidue. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (1:0 to 1:0) as eluent to give the product (7) (93mg, 22%) as a solid. LC-MS: 422.1 [M+H]⁺. ¹H-NMR (300 MHz, CDCl₃): δ6.51 (s, 1H), 5.76 (s, 1H), 4.54 (d, J=8.7 Hz, 1H), 4.25 (d, J=8.7 Hz,1H), 4.17-4.12 (m, 3H), 4.04 (d, J=6.9 Hz, 1H), 3.36-3.32 (m, 1H), 3.02(d, J=12.3 Hz, 1H), 2.47-2.40 (m, 1H), 2.32 (q, J=7.6 Hz, 2H), 2.18-2.15(m, 1H), 2.00-1.79 (m, 2H), 1.75-1.61 (m, 2H), 1.13 (t, J=7.7 Hz, 3H),1.03 (s, 6H). ¹³C-NMR (75 MHz, CDCl₃): δ 174.5, 171.0, 167.1, 83.6,62.0, 60.8, 60.2, 47.2, 36.8, 34.0, 27.7, 24.1, 23.7, 20.8, 17.6, 9.2.

Example 8 Synthesis of benzyl(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl)adipate (8)

Step 1: Synthesis of benzyl (perfluorophenyl) adipate (8a)

To a stirring solution of adipic acid monobenzyl ester (1.03 g, 4.3mmol) and pentafluorophenol (0.87 g, 4.7 mmol) in EtOAc (18.7 mL) at 0°C. was added N,N′-dicyclohexylcarbodiimide (0.97 g, 4.7 mmol). Themixture was allowed to warm to room temperature and then stirredovernight. The resulting solid was removed by vacuum filtration througha pad of Celite®. The filter cake was washed with EtOAc. The filtratewas dry-loaded on to silica gel and purified by column chromatography onsilica gel using EtOAc/hexanes (0:1 to 4:6) as eluent, to give theproduct (8a) (1.59 g, 93%) as a solid. ¹H NMR (300 MHz, CDCl₃): δ7.37-7.35 (m, 5H), 5.13 (s, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.44 (t, J=6.5Hz, 2H), 1.82-1.78 (m, 4H).

Step 2: Synthesis of benzyl (4-hydroxy-3,3-dimethylbutyl) adipate (8b)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (6a) (0.22 g, 1.8mmol) in anhydrous dichloromethane (4 mL) at ca. 0° C. (ice bath), underan atmosphere of argon, was added benzyl (perfluorophenyl) adipate (8a)(0.36 g, 0.9 mmol), Et₃N (0.25 mL, 1.8 mmol), and a catalytic amount of4-N,N-dimethylaminopyridine (small unweighed amount). The mixture wasgradually warmed to room temperature, and then at room temperatureovernight. The mixture was dry-loaded on to silica gel and purified bycolumn chromatography on silica gel using EtOAc/hexanes (0:1 to 3:7) aseluent to give the product contaminated with regio-isomeric product.This mixture was re-purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 3:7) as eluent to give pure product (8b)(113 mg 38%). ¹H-NMR (300 MHz, CDCl₃): 7.36-7.34 (m, 5H), 5.11 (s, 2H),4.14 (t, J=7.2 Hz, 2H), 3.34 (d, J=5.7 Hz, 2H), 2.38-2.31 (m, 4H),1.68-1.59 (m, 6H), 0.92 (s, 6H). The reaction could be repeated to givelarger amounts of material.

Step 3: Synthesis of benzyl (4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl)adipate (8c)

A solution of freshly distilled sulfuryl chloride (0.12 ml, 1.6 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of benzyl (4-hydroxy-3,3-dimethylbutyl) adipate (8b) (446 mg,1.3 mmol) and pyridine (0.11 mL, 1.3 mmol) in Et₂O (3.5 mL) was addeddropwise over 1 h to the cooled solution. The mixture was allowed towarm to room temperature and was stirred for 30 min (monitored by TLC,30% EA/hex). The reaction was not complete, so the mixture was recooledto −78° C., then sulfuryl chloride (0.05 mL) and pyridine (0.05 mL) wereadded. The mixture was allowed to warm to room temperature, and stirredfor 30 min. Et₂O (5 mL) was added, and the mixture was stirred for a fewmins. The mixture was filtered and the filtrate was concentrated undervacuum to give the product (8c) (446 mg, 77%). ¹H-NMR (300 MHz, CDCl₃):δ 7.39-7.29 (m, 5H), 5.11 (s, 2H), 4.22 (s, 2H), 4.15 (t, J=6.8 Hz, 2H),2.40-2.29 (m, 4H), 1.73-1.59 (m, 6H), 1.06 (s, 6H).

Step 4: Synthesis of benzyl(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)sulfonyl)oxy-3,3-dimethylbutyl)adipate (8)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (185 mg, 1.0 mmol) was dissolved in THF (9 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (1 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of argon. NaHMDS (1.0M solution in THF; 1.1 mL, 1.1 mmol) was added dropwise to the cooledsolution and stirred for 10 min. Benzyl(4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl) adipate (8c) (435 mg, 1.0mmol) in THF (1 mL) was added quickly to the mixture. The syringe wasrinsed with THF (3×0.5 mL) and this was also added to the mixture. After10 min, the mixture was allowed to warm to room temperature. Uponcompletion (30 min; TLC, 70% EtOAc/hexanes), EtOAc (10 mL) and saturatedaqueous NaHCO₃ (10 mL) were added. The aqueous and organic layers werepartitioned and the organic layer was washed with saturated aqueousNaHCO₃ (10 mL), water (3×10 mL), brine (10 mL), then dried (Na₂SO₄),filtered and concentrated under vacuum to leave a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:9 to 1:0) as eluent to give a solid. The solid wastriturated with Et₂O (2×2 mL) to give the product (8) (43 mg, 7%) as asolid [together with less pure material (99 mg, 93% purity), which wasused in the next step without further purification]. Data for the 43 mgof pure product is detailed below. LC-MS: 584.2 [M+H]⁺. ¹H-NMR (300 MHz,CDCl₃): δ 7.39-7.30 (m, 5H), 6.52 (s, 1H), 5.65 (s, 1H), 5.11 (s, 2H),4.54 (d, J=9.6 Hz, 1H), 4.24 (d, J=8.7 Hz, 1H), 4.16-4.08 (m, 3H), 4.04(d, J=7.2 Hz, 1H), 3.35-3.31 (m, 1H), 3.01 (d, J=12.3 Hz, 1H), 2.47-2.30(m, 5H), 2.18-2.12 (m, 1H), 1.99-1.77 (m, 2H), 1.74-1.65 (m, 6H), 1.03(s, 6H). ¹³C-NMR (75 MHz, CDCl₃): δ 173.34, 173.31, 171.0, 167.1, 136.1,128.7, 128.4, 128.3, 83.5, 66.4, 62.0, 60.9, 60.2, 47.2, 36.8, 34.0,24.5, 24.4, 24.2, 23.8, 20.8, 17.6.

Example 9 Synthesis of6-(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutoxy)-6-oxohexanoicacid (9)

Palladium on carbon (10% by weight; 13 mg) was added to a Parr flaskcharged with benzyl(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl)adipate (8) (93% purity; 50 mg, 0.1 mmol) in MeOH (14 mL). The mixturewas hydrogenated at 1 atm of H₂ (balloon), at room temperature for 30min (monitored by TLC, 100% EtOAc; PMA stain; LC-MS: product roomtemperature=4.66 min and m/z=494.2 [M+H]⁺, starting material roomtemperature=5.48 min and m/z=584.3 [M+H]+). The mixture was filteredthrough a pad of Celite®, and the filter cake was rinsed with MeOH (ca.20 mL). The filtrate was concentrated under vacuum, then purified bycolumn chromatography on silica gel using MeOH/CH₂Cl₂ (0:1 to 4:96) aseluent, to give the product (9) (12 mg) as a solid [ca. 73% purity byLC/MS]. LC-MS: 494.2 [M+H]⁺.

Example 10 Synthesis of methyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(10)

Step 1: Reaction to Produce methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (10a)

A solution of freshly distilled sulfuryl chloride (3.3 mL, 45.4 mmol) inEt₂O (45 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof methyl 2,2-dimethyl-3-hydroxypropionate (3.0 g, 22.7 mmol) andpyridine (2.2 mL, 27.2 mmol) in Et₂O (20 mL) was added dropwise to thesulfuryl chloride solution over 30 min. The flask was rinsed with Et₂O(3×5 mL) and the rinse was added to the reaction mixture. The mixturewas stirred at −78° C. until completion (monitored by TLC, 30% EA/hex,30 min). The precipitate was filtered, and the filtrate was concentratedunder vacuum to afford methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (10a) (5.6 g, 70% yield).The mixture was stored at −78° C. and was used immediately for the nextstep without further purification. ¹H-NMR (300 MHz, CDCl₃) δ 4.50 (s,2H), 3.74 (s, 3H), 1.31 (s, 6H).

Step 2: Reaction to Produce methyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(10)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (673 mg, 3.6 mmol) was dissolved in THF (35 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (5 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of Ar. A 1.0 Msolution of NaHMDS solution in THF (4.0 mL, 4.0 mmol) was added dropwiseto the cooled solution. After complete addition, the mixture was stirredfor 10 min. Neat methyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate(10a) (1.27 g, 3.6 mmol, 1.0 equiv., 66% pure) was added quickly to thereaction mixture. The syringe was rinsed with THF (3×2.5 mL) and therinse added to the mixture. After 10 min, the reaction mixture wasallowed to warm to 23° C. Upon completion by TLC (30 min; 70%EtOAc/hexanes), EtOAc (50 mL) and saturated aqueous NaHCO₃ (50 mL) wereadded to the reaction mixture. The layers were partitioned and theorganic layer washed with saturated aqueous NaHCO₃ (50 mL), water (3×50mL), brine (50 mL), then dried (Na₂SO₄), and concentrated under vacuumto leave a crude residue. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes as eluent (1:9 to 1:0)to give the product (10) (98 mg, 7% yield). LC-MS: 380.2 [M+H]⁺. ¹H-NMR(300 MHz, CDCl₃): δ 6.47 (s, 1H), 5.61 (s, 1H), 4.72 (d, J=9.3 Hz, 1H),4.58 (d, J=9.3 Hz, 1H), 4.18 (m, 1H), 4.05 (d, J=6.9 Hz, 1H), 3.72 (s,3H), 3.35-3.31 (m, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.47-2.41 (m, 1H),2.19-2.13 (m, 1H), 2.01-1.79 (m, 2H), 1.29 (s, 3H), 1.28 (s, 3H).¹³C-NMR (75 MHz, CDCl₃): δ 174.7, 171.1, 167.1, 80.4, 62.0, 60.2, 52.6,47.2, 43.0, 22.2, 21.8, 20.9, 17.6

Example 11 Synthesis of isopropyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(11)

Step 1: Reaction to Produce isopropyl 3-hydroxy-2,2-dimethylpropanoate(11a)

Reference is made to German Application Publication No. DE3045373. Amixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),isopropanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid; 1 mL) was heated to reflux and stirred overnight. After allowingto cool, the mixture was concentrated under vacuum and the residuepartitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (100mL). The aqueous mixture was washed with H₂O (50 mL), saturated NaHCO₃(50 mL) and brine (50 mL), then dried (Na₂SO₄), filtered andconcentrated under vacuum to leave provide the product as an oil. Theproduct (11a) was used directly in the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): δ 5.08-4.95 (m, 1H), 3.53 (fd,J=1.8 Hz, 2H), 2.49 (s, 1H), 1.25 (fd, J=2.4 Hz, 3H), 1.22 (fd, J=2.4Hz, 3H), 1.17 (s, 3H), 1.16 (s, 3H).

Step 2: Reaction to Produce isopropyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (11b)

A solution of sulfuryl chloride (2.7 mL, 37.5 mmol) in Et₂O (45 mL) wascooled to −78° C. under an atmosphere of Ar. A solution of isopropyl3-hydroxy-2,2-dimethylpropanoate (11a) (3.0 g, 18.7 mmol) and pyridine(1.82 mL, 22.5 mmol) in Et₂O (20 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×5 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion by TLC (30 min; 30% EA/hex). Theprecipitate was filtered, and the filtrate was concentrated under vacuumto afford isopropyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (11b)(4.1 g, 85% yield). The mixture was stored at −78° C. and was usedimmediately for the next step without further purification. ¹H-NMR (300MHz, CDCl₃): δ 5.10-4.98 (m, 1H), 4.49 (s, 2H), 1.29 (s, 6H), 1.26 (s,3H), 1.24 (s, 3H).

Step 3: Reaction to Produce isopropyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(11)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (673 mg, 3.6 mmol) was dissolved in THF (35 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (5 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of Ar. A 1.0Msolution of NaHMDS in THF (4.0 mL, 4.0 mmol) was added dropwise to thecooled solution and stirred for 20 min. Neat isopropyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (11b) (0.94 g, 3.6 mmol)was added quickly to the reaction mixture. The syringe was rinsed withTHF (3×3 mL) and the rinse was also added to the mixture. After 20 min,the mixture was allowed to warm to rt. Upon completion of the reactionby TLC (30 min; 70% EtOAc/hexanes), EtOAc (50 mL) and saturated aqueousNaHCO₃ (50 mL) were added to the reaction mixture. The aqueous andorganic layers were separated, and the organic layer was washed withsaturated aqueous NaHCO₃ (50 mL), water (3×50 mL), brine (50 mL), thendried (Na₂SO₄), and concentrated under vacuum to leave a crude residue.The residue was purified by column chromatography (40 g ISCO column) onsilica gel using EtOAc/hexanes (1:9 to 1:0) as eluent to give theproduct (11) (63 mg, 4%) as a solid. LC-MS: 408.2 [M+H]⁺. ¹H-NMR (300MHz, CDCl₃): δ 6.50 (s, 1H), 5.74 (s, 1H), 5.02 (quint, J=6.3 Hz, 1H),4.70 (d, J=8.7 Hz, 1H), 4.60 (d, J=9.3 Hz, 1H), 4.17 (m, 1H), 4.05 (d,J=7.2 Hz, 1H), 3.34-3.30 (m, 1H), 3.02 (d, J=11.7 Hz, 1H), 2.47-2.40 (m,1H), 2.19-2.12 (m, 1H), 2.04-1.66 (m, 2H), 1.26-1.23 (m, 12H). ¹³C-NMR(75 MHz, CDCl₃): δ 173.7, 171.1, 167.0, 80.6, 68.8, 62.0, 60.2, 47.2,42.9, 22.2, 21.7, 21.6, 20.9, 17.5.

Example 12 Synthesis of hexyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(12)

Step 1: Reaction to Produce hexyl 3-hydroxy-2,2-dimethylpropanoate (12a)

Reference is made to German Application Publication No. DE3045373. Amixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-hexanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid; 1 mL) was heated to 80° C. and stirred overnight. After allowingto cool, the mixture was concentrated under vacuum (high vacuum pumprequired) and the residue partitioned between EtOAc (100 mL) andsaturated aqueous NaHCO₃ (100 mL). The aqueous mixture was washed withH₂O (50 mL), saturated NaHCO₃ (50 mL) and brine (50 mL), then dried(Na₂SO₄), filtered and concentrated under vacuum to provide the product(12a) as an oil. The product was used directly in the next step withoutfurther purification. H-NMR (300 MHz, CDCl₃): δ 4.04-3.98 (m, 2H),3.47-3.45 (m, 2H), 2.26 (s, 1H), 1.58-1.32 (m, 2H), 1.32-1.23 (m, 6H),1.12 (s, 3H), 1.11 (s, 3H).

Step 2: Reaction to Produce hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (12b)

A solution of sulfuryl chloride (2.1 mL, 29.7 mmol) in Et₂O (40 mL) wascooled to −78° C. under an atmosphere of argon. A solution of hexyl3-hydroxy-2,2-dimethylpropanoate (12a) (3.0 g, 14.8 mmol) and pyridine(1.4 mL, 17.8 mmol) in Et₂O (15 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×5 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion by TLC (30 min; 30% EA/hex). Theprecipitate was filtered, and the filtrate was concentrated under vacuumto afford the product (12b) (3.7 g, 83% yield). The mixture was storedat −78° C. and was used immediately for the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): 4.50 (s, 2H), 4.13 (t, J=6.8 Hz,2H), 1.69-1.60 (m, 2H), 1.40-1.27 (m, 12H), 0.91-0.87 (m, 3H).

Step 3: Reaction to Produce hexyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(12)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (673 mg, 3.6 mmol) was dissolved in THF (35 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (5 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of Ar. A 1.0 Msolution of NaHMDS in THF (4.0 mL, 4.0 mmol) was added dropwise to thecooled solution and stirred for 20 min. Neat hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (12b) (1.1 g, 3.6 mmol)was added quickly to the reaction mixture. The syringe was rinsed withTHF (3×3 mL) and the rinse was also added to the mixture. After 10 min,the reaction mixture was warmed to 23° C. and stirred until the reactionwas complete as determined by TLC and LC-MS. EtOAc (50 mL) and saturatedaqueous NaHCO₃ (50 mL) were added to the mixture. The layers werepartitioned, and the organic layer was washed with saturated aqueousNaHCO₃ (50 mL), water (3×50 mL), brine (50 mL), then dried (Na₂SO₄),filtered and concentrated under vacuum to leave a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:9 to 1:0) as eluent followed by high-performance liquidchromatography to give the product (12) (44 mg, 3%) as a solid. LC-MS:450.1 [M+H]⁺. ¹H-NMR (300 MHz, CDCl₃): δ 6.49 (s, 1H), 5.71 (s, 1H),4.71 (d, J=8.7 Hz, 1H), 4.60 (d, J=9.3 Hz, 1H), 4.17-4.04 (m, 4H),3.34-3.30 (m, 1H), 3.04-3.00 (d, J=12.6 Hz, 1H), 2.47-2.40 (m, 1H),2.18-2.13 (m, 1H), 2.01-1.79 (m, 2H), 1.66-1.59 (m, 2H), 1.37-1.27 (m,12H), 0.91-0.86 (m, 3H). ¹³C-NMR (75 MHz, CDCl3): δ 174.3, 171.1, 167.0,80.5, 65.6, 62.0, 60.2, 47.2, 43.0, 31.5, 28.6, 25.6, 22.6, 22.3, 21.8,20.9, 17.6, 14.1.

Example 13 Synthesis of heptyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(13)

Step 1: Reaction to Produce heptyl 3-hydroxy-2,2-dimethylpropanoate(13a)

Reference is made to German Application Publication No. DE3045373. Amixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-heptanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid; 1 mL) was heated to 80° C. and stirred overnight. After allowingthe mixture to cool, the mixture was concentrated under vacuum (highvacuum pump required) and the residue partitioned between EtOAc (100 mL)and saturated aqueous NaHCO₃ (100 mL). The aqueous was washing with H₂O(50 mL), saturated NaHCO₃ (50 mL) and brine (50 mL), then dried(Na₂SO₄), filtered and concentrated under vacuum to provide the product(13a) as an oil. The product was used directly in the next step withoutfurther purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.31 (t, J=6.5 Hz, 2H),3.77 (s, 2H), 1.87-1.81 (m, 2H), 1.53-1.50 (m, 8H), 1.41 (s, 6H),1.12-1.08 (m, 3H).

Step 2: Reaction to Produce heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (13b)

A solution of sulfuryl chloride (2.0 mL, 27.7 mmol) in Et₂O (40 mL) wascooled to −78° C. under an atmosphere of argon. A solution of heptyl3-hydroxy-2,2-dimethylpropanoate (13a) (3.0 g, 13.9 mmol) and pyridine(1.4 mL, 16.6 mmol) in Et₂O (15 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×5 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion as monitored by TLC (30 min; 30%EA/hex). The precipitate was filtered, and the filtrate was concentratedunder vacuum to afford heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (13b) (3.3 g, 75%). Themixture was stored at −78° C. and was used immediately for the next stepwithout further purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.46 (s, 2H),4.11-4.00 (m, 2H), 1.64-1.55 (m, 2H), 1.26-1.24 (m, 8H), 0.85-0.81 (m,3H).

Step 3: Reaction to Produce heptyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(13)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (673 mg) was dissolved in THF (35 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (5 mL) and the resultingsolution was cooled to −78° C. under an atmosphere of Ar. A 1.0 Msolution of NaHMDS in THF (4.0 mL, 4.0 mmol) was added dropwise to thecooled solution and stirred for 20 min. Neat heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (13b) (1.3 g, 4.0 mmol)was added quickly to the reaction mixture. The syringe was rinsed withTHF (3×3 mL) and the rinse was also added to the mixture. After 10 min,the reaction mixture was warmed to 23° C. and stirred until complete asdetermined by TLC and LC-MS. EtOAc (50 mL) and saturated aqueous NaHCO₃(50 mL) were added to the mixture. The aqueous and organic layers werepartitioned, and the organic layer was washed with saturated aqueousNaHCO₃ (50 mL), water (3×50 mL), brine (50 mL), then dried (Na₂SO₄),filtered and concentrated under vacuum to leave a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:9 to 1:0) as eluent, followed by purification usinghigh-performance liquid chromatography to give the product (13) (65 mg,4%) as a solid. LC-MS: 464.3 [M+H]⁺. ¹H-NMR (300 MHz, CDCl₃): δ 6.48 (s,1H), 5.71 (s, 1H), 4.71 (d, J=9.6 Hz, 1H), 4.60 (d, J=9.3 Hz, 1H),4.18-4.04 (m, 4H), 3.34-3.29 (m, 1H), 3.02 (d, J=11.7 Hz, 1H), 2.47-2.40(m, 1H), 2.19-2.11 (m, 1H), 2.01-1.79 (m, 2H), 1.66-1.59 (m, 2H),1.37-1.26 (m, 14H), 0.90-0.86 (m, 3H). ¹³C-NMR (75 MHz, CDCl₃): δ 174.3,171.1, 167.0, 80.5, 65.6, 62.0, 60.2, 47.2, 43.0, 31.8, 29.0, 28.6,25.9, 22.7, 22.2, 21.8, 20.9, 17.6, 14.2.

Example 14 Synthesis of tert-butyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(14)

Step 1 and Step 2: Reaction to Produce tert-butyl3-hydroxy-2,2-dimethylpropanoate (14a)

The compound was synthesized in accordance with PCT InternationalApplication Publication No. WO 2007116922. Sodium hydride (60% inmineral oil; 2.0 g) was added to a cooled solution of tert-butyl methylmalonate (4 g) in THF (100 mL) at 0° C. under an atmosphere of Ar. Themixture was stirred at 0° C. for 10 min. MeI (3.2 mL) was added to themixture and the stirring was continued for 3 h (by this time the mixturewas at room temperature). Brine and EtOAc were added to the mixture, andthe organic layer was separated, dried (Na₂SO₄), filtered andconcentrated under vacuum to give the product (ca. 4.5 g), which wasused directly in the next step.

Solid lithium tri-tert-butoxy-aluminohydride (7.1 g, 28 mmol) was addedportion-wise over 15 min to a solution of tert-butyl methyl2,2-dimethyl-malonate (2.2 g) in THF (100 mL) under an atmosphere of Ar.The mixture was then heated to reflux and stirred overnight. Aftercooling to room temperature, a saturated solution of NH₄Cl and EtOAcwere added, and the aqueous and organic layers were separated. Theorganic layer was washed with H₂O and brine, then dried (Na₂SO₄),filtered and concentrated under vacuum to provide a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 3:7) as eluent to give the product (14a) (900 mg)as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 3.50 (d, J=5.1 Hz, 2H), 2.53 (t,J=6.5 Hz, 1H), 1.45 (s, 9H), 1.14 (s, 6H)

Step 3: Reaction to Produce tert-butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (14b)

A solution of sulfuryl chloride (0.31 mL, 4.2 mmol) in Et₂O (6 mL) wascooled to −78° C. under an atmosphere of Ar. A solution of tert-butyl3-hydroxy-2,2-dimethylpropanoate (14a) (0.49 g, 2.8 mmol) and pyridine(0.25 ml, 3.1 mmol) in Et₂O (6 mL) was added dropwise to the sulfurylchloride solution over the course of 10 min. The mixture was stirred at−78° C. for 90 min and allowed to warm to 23° C. after TLC revealed thatthe reaction had not proceeded to completion (10% EtOAc/hexanes). Themixture was re-cooled to −78° C. and an additional 1 equivalent ofsulfuryl chloride was added, stirred for 10 min, and the mixture allowedto warm to 23° C. (note: the mixture was allowed to stir for a total of1 h after the addition and during the warming period). The precipitatewas filtered, and the filtrate was concentrated under vacuum to givetert-butyl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (14b) (961 mg,yield assumed quantitative) as a clear, oil. ¹H-NMR (300 MHz, CDCl₃): δ4.46 (fd, J=1.5 Hz, 2H), 1.47 (fd, J=1.2 Hz, 9H), 1.27 (s, 6H).

Step 4: Reaction to Produce tert-butyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(14)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (463 mg, 2.5 mmol) was dissolved in THF (25 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (1.5 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of Ar. A 1.0 M NaHMDSsolution in THF (2.8 mL, 2.8 mmol) was added dropwise to the cooledsolution, and the mixture stirred for 10 min. Neat tert-butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (14b) (0.75 g, 2.8 mmol)was added quickly to the reaction mixture. The syringe was rinsed withTHF (3×3 mL) and these rinses were also added to the mixture quickly.After 20 min, the reaction mixture was allowed to warm to 23° C. Afterstirring for 70 min, the reaction was complete as determined by TLC (70%EA/hexanes). The mixture was cooled to 0° C., diluted with EtOAc (50mL), and quenched with saturated aqueous NaHCO₃ (50 mL). The aqueous andorganic layers were partitioned, and the organic layer was washed withsaturated aqueous NaHCO₃ (50 mL), water (3×50 mL), and brine (50 mL),then dried (Na₂SO₄), and concentrated under vacuum to provide a cruderesidue. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (1:9 to 1:0) as eluent to give the product (14) (368mg, 35% yield) as a solid. LC-MS: 422.1 [M+H]⁺. ¹H-NMR (300 MHz, CDCl₃):δ 6.50 (s, 1H), 5.85 (s, 1H), 4.66 (d, J=9 Hz, 1H), 4.56 (d, J=8.7 Hz,1H), 4.17 (s, 1H), 4.04 (d, J=6.9 Hz, 1H), 3.33-3.29 (m, 1H), 3.02 (d,J=12 Hz, 1H), 2.46-2.39 (m, 1H), 2.17-2.12 (m, 1H), 2.00-1.79 (m, 2H),1.45 (s, 9H), 1.23 (s, 3H), 1.21 (s, 3H). ¹³C-NMR (75 MHz, CDCl₃): δ173.3, 171.1, 167.0, 81.6, 80.9, 62.0, 60.2, 47.2, 43.4, 28.0, 22.2,21.6, 20.8, 17.6.

Example 15 Synthesis of 2-methoxyethyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(15)

Step 1: Reaction to Produce 2-methoxyethyl3-hydroxy-2,2-dimethylpropanoate (15a)

3-Hydroxy-2,2-dimethylpropanoic acid (1.2 g, 10.3 mmol) and Cs₂CO₃ (3.4g, 10.4 mmol) were suspended in DMF (25 mL) at 23° C., then 2-bromoethylmethyl ether (1.0 mL, 10.4 mmol) was added. The resulting mixture wasstirred at 70° C. overnight. After cooling, the mixture was filteredthrough a pad of Celite®. The filtrate was diluted with EtOAc (150 mL),and the mixture washed with water (3×100 mL) and brine, then dried(Na₂SO₄), filtered and concentrated to leave a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:4 to 4:1) as eluent to provide the product (15a) (1.3g, crude weight) as an oil. ¹H-NMR (300 MHz, CDCl₃): δ 4.28 (t, J=4.8Hz, 2H), 3.62-3.55 (m, 4H), 3.38 (s, 3H), 2.65 (t, J=6.0 Hz, 1H), 1.21(s, 6H).

Step 2: Reaction to Produce 2-methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (15b)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.8 mmol) inEt₂O (7.0 mL) was cooled to −78° C. under an atmosphere of Ar. Asolution of 2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate (15a) (0.48g, 2.7 mmol) and pyridine (0.24 mL, 3.0 mmol) in Et₂O (1 mL) was addeddropwise to the sulfuryl chloride solution over the course of 11 min.The flask was rinsed with Et₂O (3×1 mL) which was also added to thereaction mixture. The mixture was stirred at −78° C. until completion(monitored by TLC, 30% EtOAc/hex, 30 min). The precipitate was filtered,and the filtrate was concentrated under vacuum to afford the product(15b) (0.5 g, 67%) as an oil, which was used directly in the next stepwithout further purification [Note: ¹HNMR indicated desired product withresidue of pyridine and along with starting material].

Step 3: Reaction to Produce 2-methoxyethyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(15)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (162 mg, 0.9 mmol) was dissolved in THF (2.5 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (0.3 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of Ar. A 1.0 Msolution of NaHMDS in THF (1.0 mL, 1.0 mmol) was added dropwise to thecooled solution and the mixture stirred for 10 min. 2-Methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (15b) (0.3 g, 1.1 mmol)in THF (2 mL) was added quickly to the reaction mixture. After 10 min at−78° C., the mixture was allowed to warm to 23° C. and stirred for 30min. The mixture was diluted with EtOAc (40 mL) and water. The aqueousand organic layers were partitioned, and the organic layer was washedwith water (3×20 mL), and brine (50 mL), then dried (Na₂SO₄), filteredand concentrated under vacuum to leave a crude residue. The cruderesidue was purified by column chromatography on silica gel (4 g column)using EtOAc/hexanes (3:7 to 1:0) as eluent to give an impure solid. Theproduct was dissolved in Et₂O (20 mL) with the aid of sonication, andprecipitated with hexanes. The resulting solid was filtered, and driedunder vacuum to provide the product (15) (72 mg, 19.4%) as a solid.LCMS: m/z=424.3 [M+H]⁺. ¹H-NMR (300 MHz, CDCl₃): δ 6.48 (br. s, 1H),5.56 (br. s, 1H), 4.62 (dd, J=28.8, 8.7 Hz, 2H), 4.33-4.22 (m, 2H), 4.17(br. s, 1H), 4.05 (d, J=6.9 Hz, 1H), 3.60 (t, J=4.6 Hz, 2H), 3.38 (s,3H), 3.33 (d, J=11.1 Hz, 1H), 3.02 (d, J=12.0 Hz, 1H), 2.46-2.41 (m,1H), 2.18-2.13 (m, 1H), 1.98-1.84 (m, 2H), 1.31 (s, 3H), 1.29 (s, 3H).¹³C-NMR (75 MHz, CDCl₃), δ 174.1, 170.8, 166.9, 80.2, 70.2, 64.1, 61.8,60.0, 59.0, 47.1, 42.9, 22.1, 21.6, 20.7, 17.4.

Example 16 Synthesis of oxetan-3-yl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(16)

Step 1: Reaction to Produce oxetan-3-yl 3-hydroxy-2,2-dimethylpropanoate(16a)

3-Hydroxy-2,2-dimethylpropanoic acid (4.7 g, 40 mmol) and Cs₂CO₃ (13.0g, 40 mmol) were suspended in DMF (100 mL) at 23° C., then 3-iodooxetane(7.4 g, 40 mmol) was added. The resulting mixture was stirred at 70° C.overnight. After cooling, the mixture was diluted with EtOAc (150 mL),and the mixture washed with water (3×100 mL) and brine, then dried(Na₂SO₄), filtered and concentrated to provide a crude residue. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes as eluent to give the product (16a) (3.6 g, 51%) as anoil.

Step 2: Reaction to Produce oxetan-3-yl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (16b)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.7 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof oxetan-3-yl 3-hydroxy-2,2-dimethylpropanoate (16a) (0.46 g, 2.6 mmol)and pyridine (0.2 mL, 2.7 mmol) in Et₂O (2 mL) was added dropwise to thesulfuryl chloride solution over the course of 11 min. The flask wasrinsed with Et₂O (3×1 mL) which was also added to the reaction mixture.The mixture was stirred at −78° C. until completion (monitored by TLC,30% EtOAc/hex, 30 min). The precipitate was filtered, and the filtratewas concentrated under vacuum to afford the product (16b) (0.5 g, 69%)as an oil, which was used directly in the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃): δ 5.50-5.46 (m, 1H), 4.94-4.89(m, 2H), 4.65-4.60 (m, 2H), 4.52 (s, 2H), 1.72 (br. s, 1H), 1.36 (s,6H).

Step 3: Reaction to Produce oxetan-3-yl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(16)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (200 mg, 1.1 mmol) was dissolved in THF (3 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (2 mL), DMPU was added, andthe resulting solution was cooled to −78° C. under an atmosphere of Ar.A 1.0 M solution of NaHMDS in THF (1.2 mL, 1.2 mmol) was added dropwiseto the cooled solution, and the mixture stirred for 10 min. A solutionof oxetan-3-yl 3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (16b)(0.37 g, 1.4 mmol) in THF (2 mL) was added quickly to the reactionmixture. After stirring at −78° C. for 10 min, the mixture was allowedto warm to 23° C. and stirred for a total of 1 h. The mixture wasdiluted with EtOAc (40 mL) and H₂O. The aqueous and organic layers werepartitioned, and the organic layer washed with H₂O (3×20 mL), brine (50mL), then dried (Na₂SO₄), filtered and concentrated under vacuum to givea crude residue. The crude residue was purified by column chromatographyon silica gel (4 g column) using EtOAc/hexanes (3:7 to 1:0) as eluent togive an oil. The oil was triturated with Et₂O with the aid ofsonication, and the filter cake was washed with Et₂O to provide theproduct (16) (170 mg, 37%) as a solid. LCMS: m/z=422.3 [M+H]⁺. ¹H-NMR(300 MHz, CDCl₃): δ 6.48 (br. s, 1H), 5.54 (br. s, 1H), 5.48-5.44 (m,1H), 4.89 (t, J=7.4 Hz, 2H), 4.79 (d, J=8.7 Hz, 1H), 4.66-4.58 (m, 3H),4.18 (br. s, 1H), 4.05 (d, J=6.9 Hz, 1H), 3.33 (d, J=12.3 Hz, 1H),2.44-2.42 (m, 1H), 2.20-2.16 (m, 1H), 2.00-1.80 (m, 2H), 1.32 (s, 3H),1.31 (s, 3H). 13C-NMR (75 MHz, CDCl₃): δ 173.4, 170.8, 167.0, 80.0,68.6, 76.6, 61.9, 60.2, 47.1, 42.7, 21.9, 21.6, 20.7, 17.4.

Example 17 Synthesis of ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate(17)

Step 1: Reaction to Produce ethyl1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (17a)

A solution of freshly distilled sulfuryl chloride (77 μL, 1.1 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (0.2 g, 1.0 mmol) andpyridine (85 μL, 1.1 mmol) in Et₂O (2 mL) was added dropwise to thesulfuryl chloride solution over 11 min. The flask was rinsed with Et₂O(3×1 mL) and the rinse added to the reaction. The mixture was stirred at−78° C. until completion (ca. 30 min; monitored by TLC, 30% EtOAc/hex).The precipitate was filtered, and the filtrate was concentrated undervacuum to afford the title compound as an oil, which was used directlyin the next step without purification. A second batch using 476 mg ofthe starting alcohol, afforded 600 mg of the product (17a)(approximately, 85% purity by ¹H-NMR).

Step 2: Reaction to Produce ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate(17)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.33 g, 1.8 mmol) was dissolved in THF (7 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (3.5 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of Ar. A 1.0 Msolution of NaHMDS in THF (1.8 mL, 1.8 mmol) was added dropwise over 20min, and the mixture stirred for 10 min. Ethyl1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (17a) (0.51 g, 1.8mmol) in THF (2 mL) was added quickly to the reaction mixture. After 10min stirring at −78° C. the mixture was allowed to warm to 23° C. andstirred for a total of 1 h. The reaction mixture was diluted with EtOAc(40 mL) and H₂O at −60° C. The aqueous and organic layers werepartitioned, and the organic layer was washed with H₂O (3×20 mL), andbrine (50 mL), then dried (Na₂SO₄), filtered and concentrated undervacuum to give the crude residue (330 mg). The oil was purified bycolumn chromatography on silica gel (4 g column) using EtOAc/hexanes(3:7 to 1:0) as eluent, followed by purification using preparative HPLC(10-90% MeCN/H₂O over 20 min using UV detection at 254/220 nM) to givethe product (17) (223 mg, 34%) as a solid. LCMS: m/z=434.3 [M+H]⁺.¹H-NMR (300 MHz, CDCl₃): δ 6.50 (br. s, 1H), 5.80 (br.s, 1H), 4.66 (dd,J=48.6, 12.8 Hz, 2H), 4.21-4.15 (m, 3H), 4.04 (d, J=6.9 Hz, 1H), 3.31(d, J=3.0 Hz, 1H), 3.01 (d, J=11.7 Hz, 1H), 2.44-2.39 (m, 1H), 2.16-1.78(m, 5H), 1.57-1.39 (m, 8H), 1.27 (t, J=7.1 Hz, 3H). ¹³C-NMR (75 MHz,CDCl₃): δ 173.2, 171.0, 167.0, 80.2, 61.8, 61.1, 60.1, 47.1, 30.4, 30.0,25.4, 22.2, 22.0, 20.7, 17.4, 14.1.

Example 18 Synthesis of ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopentane-1-carboxylate(18)

Step 1: Reaction to Produce ethyl1-(((chlorosulfonyl)oxy)methyl)cyclopentane-1-carboxylate (18a)

A solution of freshly distilled sulfuryl chloride (200 μL, 2.7 mmol) inEt₂O (3 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof ethyl 1-(hydroxymethyl)cyclopentanecarboxylate (0.48 g, 2.7 mmol) andpyridine (222 μL, 2.7 mmol) in Et₂O (2 mL) was added dropwise to thesulfuryl chloride solution over 7 min. The flask was rinsed with Et₂O(2×1 mL) and both rinses were added to the reaction mixture. The mixturewas stirred at −78° C. for 1.5 h. The precipitate was filtered, and thefilter-cake washed with Et₂O (4 mL). The filtrate was concentrated undervacuum to afford the title compound (18a) as an oil, which was useddirectly in the next step without further purification.

Step 2: Reaction to Produce ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopentane-1-carboxylate(18)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (200 mg, 1.1 mmol) was dissolved in THF (5 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (2 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of Ar. A 1.0 Msolution of NaHMDS in THF (1.3 mL, 1.3 mmol. Note: since the sulfonylchloride contains about 20% starting alcohol, additional 0.2 eq NaHMDSwas added) was added dropwise over 10 min. Note: the reaction mixturewas immersed and lifted from the cooling bath, to get the solution tostir, otherwise it was a gel. Ethyl1-(((chlorosulfonyl)oxy)methyl)cyclopentanecarboxylate (18a) (0.47 g,1.7 mmol) in THF (2×1 mL) was added quickly to the reaction mixture.After 10 min, the mixture was allowed to warm to 23° C. and stirred fora total of 2 h. The reaction mixture was diluted with EtOAc (40 mL) andbrine at −60° C. The aqueous and organic layers were partitioned, andthe organic layer was dried (Na₂SO₄), filtered and concentrated undervacuum to leave a crude residue. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (3:7 to 1:0) as eluent,followed-by reverse-phase preparative HPLC to afford the title compound(18) (62 mg, 14%) as a solid. LCMS: m/z=420.3 [M+H]⁺. ¹H-NMR (300 MHz,CDCl₃): δ 6.55 (br. s, 1H), 6.15 (br. s, 1H), 4.69 (dd, J=20.9, 9.3 Hz,2H), 4.20-4.10 (m, 3H), 4.02 (d, J=6.6 Hz, 1H), 3.29 (d, J=12.3 Hz, 1H),3.01 (d, J=11.7, 1H), 2.40-2.36 (m, 1H), 2.14-1.66 (m, 11H), 1.24 (t,J=7.4 Hz, 3H). ¹³C-NMR (75 Hz, CDCl₃): δ 174.4, 171.2, 167.0, 78.9,61.8, 61.2, 60.1, 53.0, 47.0, 33.9, 32.9, 25.6, 25.5, 20.7, 17.5, 14.1.

Example 19 Synthesis of ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate(19)

Step 1: Reaction to Produce ethyl1-(((chlorosulfonyl)oxy)methyl)cyclobutanecarboxylate (19a)

A solution of freshly distilled sulfuryl chloride (451 μL, 6.2 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of Ar. A solutionof ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (1.0 g, 6.1 mmol) andpyridine (500 μL, 6.2 mmol) in Et₂O (10 mL) was added dropwise to thesulfuryl chloride solution over the course of 11 min. The flask wasrinsed with Et₂O (3×1 mL), which was also added to the reaction mixture.The mixture was stirred at −78° C., which was allowed to warm to ambienttemp. within 4 h. The precipitate was filtered, and the filtrate wasconcentrated under vacuum to afford the title compound (1.2 g, 76%) asan oil, which was used directly in the next step without furtherpurification. Note: ¹HNMR indicated desired product (19a), together withstarting material.

Step 2: Reaction to Produce ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate(19)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.33 g, 1.8 mmol) was dissolved in THF (8 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (2 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A 1.0 Msolution of NaHMDS in THF (2 mL, 2.1 mmol. Note: since the sulfonylchloride contains about 30% starting alcohol, an additional 0.3 eqNaHMDS was added.) was added dropwise over 10 min. Ethyl1-(((chlorosulfonyl)oxy)methyl)cyclobutanecarboxylate (19a) (1.0 g, 3.9mmol) in THF (2×1 mL) was added quickly to the reaction mixture. After10 min, the mixture was allowed to warm to 23° C. and stirred for 1 h.The mixture was diluted with EtOAc (40 mL) and H₂O at −60° C. Theaqueous and organic layers were partitioned, and the organic layer waswashed with brine, dried (Na₂SO₄), filtered and concentrated undervacuum to give a crude residue. The oil was purified by preparative HPLCto give a solid (303 mg). The solid was dissolved in DCM and filteredthrough a filtered syringe, to give the product (19) (273 mg, 35%) as asolid. LCMS: m/z=406.1 [M+H]⁺. ¹H-NMR (300 MHz, CDCl₃): δ 6.57 (br. s,1H), 6.28 (br. s, 1H), 4.85 (dd, J=63.9, 9.3 Hz, 2H), 4.30-4.13 (m, 3H),4.01 (d, J=7.2 Hz, 1H), 3.27 (d, J=10.8 Hz, 1H), 3.01 (d, J=11.7 Hz,1H), 2.50-2.35 (m, 3H), 2.13-1.76 (m, 8H), 1.24 (t, J=7.3 Hz, 3H).¹³C-NMR (75 MHz, CDCl₃): δ173.1, 171.3, 167.2, 77.9, 61.8, 61.2, 60.7,60.1, 47.0, 46.3, 27.1, 26.1, 20.7, 17.5, 15.6, 14.0.

Example 20 Synthesis of ethyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate(20)

Step 1: Synthesis of(1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (20a)

A solution of distilled sulfuryl chloride (0.61 mL, 7.5 mmol) in Et₂O(10 mL) was cooled to −78° C. under nitrogen. A solution of ethyl3-hydroxy-2,2-dimethylpropanoate (2a) (1.0 g, 6.8 mmol) and pyridine(0.55 mL, 6.8 mmol) in Et₂O (2.0 mL) was then added dropwise over 1 hvia a syringe. The reaction was stirred at −78° C. for 1 h, and themixture was allowed to warm to room temperature and stirred foradditional 2 h. After the mixture was filtered, the filtrate wasconcentrated under vacuum to give the product (20a) as a colorlessliquid (1.46 g, yield 87%). ¹H NMR (300 MHz, CDCl₃): δ 4.50 (s, 2H),4.19 (q, J=6.9 Hz, 2H), 1.31 (s, 6H), 1.28 (t, J=6.9 Hz, 3H).

Step 2: Synthesis of tert-butyl4-((1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(20b)

To a mixture of(1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (20a) (10 g, 36.2 mmol), tert-butyl 4-aminopiperidine-1-carboxylate(7.26 g, 36.2 mmol) in DCM (200 mL) was added HATU (13.76 g, 36.2 mmol)and DIPEA (6.31 mL, 36.2 mmol). The reaction was stirred at roomtemperature overnight. The mixture was washed with saturated NH₄Clsolution, water and brine. The organic layer was dried with anhydrousNa₂SO₄, filtered, and concentrated under vacuum to give a crude residue.The residue was purified by silica gel column chromatography usingEtOAc/hexane (1:1) as eluent to give the product (20b) (10.3 g, yield62%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 7.36-7.44 (m, 5H),6.55 (d, 1H, J=8.1 Hz), 5.05 (d, 1H, J=11.7 Hz), 4.90 (d, 1H, J=11.1Hz), 4.02 (br, s, 1H), 3.87-3.99 (m, 2H), 3.29 (s, 1H), 3.01 (d, 1H),2.85 (t, 2H), 2.64 (d, 1H), 2.37 (dd, 1H), 1.84-2.05 (m, 4H), 1.55-1.67(m, 2H), 1.45 (s, 9H), 1.23-1.36 (m, 2H). MS (ESI) C₂₄H₃₄N₄O₅=459.1(M+1)⁺.

Step 3: Synthesis of tert-butyl4-((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(20c)

To a solution of tert-butyl4-((1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(20b) (0.6 g, 1.31 mmol) in MeOH (6 mL) was added 10% palladium oncarbon (0.2 g). The reaction mixture was stirred under 1 atm hydrogenpressure for 1 h. After the mixture was filtered through a pad ofCelite®, the filtrate was concentrated under vacuum to give a crudeproduct (20c) (0.48 g, yield 100%) that was used directly for the nextstep. ¹H NMR (300 MHz, CDCl₃): δ 6.62 (d, 1H, J=7.8 Hz), 3.86-4.01 (m,4H), 3.75 (s, 1H), 3.17 (d, 1H), 2.91 (t, 2H), 2.81 (d, 1H), 2.42 (m,1H), 2.13 (m, 1H), 1.88 (m, 4H), 1.74 (m, 1H), 1.45 s, 9H), 1.31 (m,2H).

Step 4: Synthesis of tert-butyl4-((1R,2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(20d)

tert-Butyl4-((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(20c) (1.31 mmol) was dissolved in THF (7.0 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (3 mL), and the resultingsolution was cooled to −78° C. under a nitrogen atmosphere. A solutionof NaHMDS in THF (1M, 1.31 mL, 1.31 mmol) was added dropwise, and themixture was stirred at −78° C. for 10 min. A solution of ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) (352 mg, 1.44 mmol)in THF (1 mL) was then added to the reaction mixture via syringe. After10 min at −78° C., the reaction mixture was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was diluted withEtOAc and washed with saturated NaHCO₃, water, and brine. The organiclayer was dried with anhydrous Na₂SO₄, filtered, and concentrated undervacuum to give a crude residue. The residue was purified by silica gelcolumn chromatography using EtOAc/hexane (1:1) as eluent to give theproduct (20d) (330 mg, yield 44%) as a white foam. ¹H NMR (300 MHz,CDCl₃): δ 6.44 (d, 1H, J=8.1 Hz), 4.59-4.73 (dd, 2H, J=8.7 Hz),3.89-4.23 (m, 7H), 3.28 (d, 1H), 2.83-2.92 (m, 3H), 2.42-2.49 (m, 1H),2.14-2.17 (m, 1H), 1.80-1.97 (m, 4H), 1.46 (s, 9H), 1.58-1.23 (m, 11H).MS (ESI) C₂₄H₄₀N₄O₁₀S=577 (M+1)⁺.

Step 5: Synthesis of ethyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate(TFA Salt) (20)

To a mixture of tert-butyl4-((1R,2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(20d) (240 mg, 0.42 mmol) in DCM (1.4 mL) was added trifluoroacetic acid(1.4 mL) at −10° C. The reaction was stirred at −10° C. for 30 min.LC/MS analysis indicated that the stating material was completelyconsumed. The mixture was concentrated under vacuum to give a cruderesidue. The residue was purified by prep-HPLC on C18 column elutingwith MeCN/H₂O containing 0.1% TFA (5-100%) to give the title compound(20) (103 mg, yield 42%) as an off-white powder. ¹H NMR (300 MHz,CDCl₃): δ 9.42 (br s, 1H), 9.06 (br s, 1H), 6.71 (d, 1H, J=7.8 Hz),4.57-4.73 (dd, 2H, J=9.0 Hz), 3.99-4.19 (m, 5H), 3.48 (d, 2H), 3.26 (d,1H), 3.00 (m, 2H), 2.88 (d, 1H), 1.82-2.39 (m, 7H), 1.23-1.30 (m, 9H).¹³C NMR (75 MHz, CDCl₃): δ 174.5, 168.9, 167.3, 80.8, 62.0, 61.6, 60.4,46.8, 44.9, 43.6, 43.3, 28.7, 22.3, 21.9, 20.9, 18.0, 14.4. ¹⁹F NMR (282MHz, CDCl₃): δ −75.8. MS (ESI) C₁₉H₃₂N₄O₈S=477 (M+1)⁺.

Analytical HPLC was performed on Agilent 1200 system using a Phenomenex®C18 column (150×4.6 mm i.d.). The mobile phase was a linear gradient ofMeCN and water (0.1% TFA, 5% MeCN to 100% MeCN in 15 min). The flow ratewas maintained at 1 mL/min and the eluent was monitored with UV detectorat 220 and 254 nm. HPLC retention time: 7.31 min.

Example 21 Synthesis of 2-methoxyethyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate(21)

Step 1: Synthesis of 2-methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (21a)

A solution of distilled sulfuryl chloride (0.51 mL, 6.2 mmol) in Et₂O(10 mL) was cooled to −78° C. under nitrogen. A solution of2-methoxyethyl 3-hydroxy-2,2-dimethylpropanoate (15a) (1.0 g, 5.68 mmol)and pyridine (0.46 mL, 5.68 mmol) in Et₂O (2.0 mL) was then addeddropwise over 1 h via a syringe. The reaction was stirred at −78° C. for1 h, and then the mixture was allowed to warm to room temperature andstirred for 2 h. After the mixture was filtered, the filtrate wasconcentrated under vacuum to give the product (21a) as a colorlessliquid (1.5 g, yield 96%). ¹H NMR (300 MHz, CDCl₃): δ 4.40 (s, 2H), 4.29(t, 3H), 3.59 (t, 3H), 3.37 (s, 3H), 1.32 (s, 6H).

Step 2: Synthesis of tert-butyl4-((1R,2S,5R)-6-(((3-(2-methoxyethoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(21b)

tert-Butyl4-((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(20c) (3.26 mmol) was dissolved in THF (14 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 mL), and the resultingsolution was cooled to −78° C. under a nitrogen atmosphere. A solutionof NaHMDS in THF (1M, 3.59 mL, 3.59 mmol) was added dropwise, and themixture was stirred at −78° C. for 10 min. A solution of 2-methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (21a) (878 mg, 3.59 mmol)in THF (2 mL) was then added to the reaction mixture via a syringe.After 10 min at −78° C., the reaction mixture was allowed to warm toroom temperature and stirred overnight. The reaction mixture was dilutedwith EtOAc and washed with saturated NaHCO₃, water, and brine. Theorganic layer was dried with anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to give a crude residue. The residue waspurified by silica gel column chromatography using EtOAc/hexane (1:1) aseluent to give the product (21b) (0.96 g, yield 48%) as a white foam. MS(ESI) C₂₅H₄₂N₄O₁₁S=607.0 (M+1)⁺.

Step 3: Synthesis of 2-methoxyethyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate(TFA Salt) (21)

To a mixture of tert-butyl4-((1R,2S,5R)-6-(((3-(2-methoxyethoxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.2.1]octane-2-carboxamido)piperidine-1-carboxylate(21b) (0.86 g, 1.42 mmol) in DCM (4.3 m) was added trifluoroacetic acid(4.3 mL) at −10° C. The reaction mixture was stirred at −10° C. for 30min. LC/MS analysis indicated that the stating material was completelyconsumed. The mixture was concentrated under vacuum to give a cruderesidue. The residue was purified by prep-HPLC on a C18 column elutingwith MeCN/H₂O containing 0.1% TFA (5-75%) to give the title compound(21) (513 mg, yield 58%) as a yellow powder. ¹H NMR (300 MHz, CDCl₃): δ9.09 (br s, 1H), 8.75 (br s, 1H), 6.83 (d, 1H, J=7.8 Hz), 4.59-4.71 (dd,2H, J=9.3 Hz), 3.99-4.36 (m, 5H), 3.60 (m, 2H), 3.50 (d, 2H), 3.39 (s,3H), 3.30 (d, 1H), 3.02 (m, 2H), 2.89 (d, 1H), 1.87-2.40 (m, 7H),1.25-1.30 (m, 9H). ¹³C NMR (75 MHz, CDCl₃): δ 174.4, 168.9, 167.4, 80.6,70.6, 64.5, 62.0, 60.4, 59.3, 46.8, 44.9, 43.6, 43.2, 28.7, 22.4, 21.8,20.9, 18.0. 19F NMR (282 MHz, CDCl₃): δ −75.8. MS (ESI) C₂₀H₃₄N₄O₉S=507(M+1)⁺. HPLC retention time (MeCN/H₂O in 0.1% TFA): 6.75 min.

Example 22 Synthesis of4-((1R,2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium2,2,2-trifluoroacetate (22)

Step 1: Synthesis of hexyl 3-hydroxy-2,2-dimethylpropanoate (22a)

A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-hexanol (70 mL) and concentrated sulfuric acid (or fuming sulfuricacid, 1 mL) was heated to 80° C. and stirred overnight. After allowingto cool, the mixture was concentrated under vacuum (high vacuum pumprequired) and the residue was then partitioned between EtOAc (100 mL)and saturated aqueous NaHCO₃ (100 mL). The aqueous phase was washed withH₂O (50 mL), saturated NaHCO₃ (50 mL) and brine (50 mL), and then driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum to providethe product as an oil. The product was difficult to purify using silicagel chromatography; and therefore the product was distilled under highvacuum at 47° C. to provide 4.92 g of the pure ester product (22a)(yield 61%). ¹H NMR (300 MHz, CDCl₃) δ 4.10 (td, J=6.7, 1.3 Hz, 2H),3.55 (d, J=5.1 Hz, 2H), 2.42 (s, 1H), 1.64 (s, 1H), 1.72-1.56 (m, 1H),1.35 (s, 1H), 1.31 (s, 6H), 1.27-1.11 (m, 6H), 0.95-0.84 (m, 3H). MS(ESI) C₁₁H₂₂O₃=203 (M+1)⁺.

Step 2: Synthesis of hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (22b)

A solution of freshly distilled sulfuryl chloride (0.60 mL, 7.4 mmol) inEt₂O (10 mL) was cooled to −78° C. under an atmosphere of N₂. A solutionof hexyl 3-hydroxy-2,2-dimethylpropanoate (22a) (1.0 g, 4.94 mmol) andpyridine (0.48 mL, 5.93 mmol) in Et₂O (5 mL) was added dropwise to thesulfuryl chloride solution over the course of 20 min. The flask wasrinsed with Et₂O (3×1 mL) and the rinse added to the reaction mixture.The mixture was stirred at −78° C. until completion by TLC (30 min; 30%EA/hexane). The precipitate was filtered, and the filtrate wasconcentrated under vacuum to afford the crude product (22b) as a solidfoam and was used in the next step without further purification. ¹H-NMR(300 MHz, CDCl₃): δ 4.50 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 1.69-1.60 (m,2H), 1.40-1.27 (m, 12H), 0.91-0.87 (m, 3H).

Step 3: Synthesis of tert-butyl4-((1R,2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(22d)

The hydroxamic acid (2.39 mmol) was dissolved in THF (12 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (3.4 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of N₂. A solution ofNaHMDS in THF (2.4 mL, 1.0 M, 2.4 mmol) was added dropwise to and themixture stirred for 20 min. Neat hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (22b) (0.973 g, 2.64mmol) was added quickly to the reaction mixture. The syringe was rinsedwith THF (3×4 mL) and the rinse was also added to the mixture. After 10min, the reaction mixture was warmed to room temperature and stirreduntil complete as determined by TLC and LC-MS. EtOAc (30 mL) andsaturated aqueous NaHCO₃ (30 mL) were added to the mixture. The layerswere partitioned, and the organic layer was washed with saturatedaqueous NaHCO₃ (30 mL), water (3×20 mL), and brine (30 mL), and thendried (Na₂SO₄), filtered and concentrated under vacuum to leave a cruderesidue. The residue was purified by silica gel column chromatographyusing EtOAc/hexane (1:9 to 1:0) as eluent, followed by high-performanceliquid chromatography to give the product (22d) (740 mg, yield 49% for 3steps) as a solid foam. ¹H NMR (300 MHz, CDCl₃) δ6.43 (d, J=8.2 Hz, 1H),4.76-4.64 (m, 1H), 4.60 (d, J=9.0 Hz, 1H), 4.19-4.03 (m, 5H), 3.98 (d,J=7.5 Hz, 2H), 3.28 (d, J=12.0 Hz, 1H), 2.90 (d, J=12.0 Hz, 2H), 2.45(dd, J=14.8, 6.2 Hz, 1H), 2.14 (s, 1H), 1.97-1.84 (m, 3H), 1.62 (q,J=7.0 Hz, 11H), 1.46 (s, 9H), 1.34-1.19 (m, 14H), 0.88 (d, J=7.0 Hz,3H). MS (ESI) C₂₈H₄₈N₄O₁₀S=633 (M+1)⁺.

Step 4: Synthesis of4-((1R,2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium2,2,2-trifluoroacetate (22)

tert-Butyl4-((1R,2S,5R)-6-(((3-(hexyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(22d) (300 mg, 0.474 mmol) was dissolved in DCM (2 mL) and cooled to−10° C. To the solution was added TFA (2 mL) dropwise. The reaction wasmonitored with LCMS or TLC until completion (ca. 10 min). The solventwas removed in vacuo and the residue was purified using prep-HPLC withMeCN/H₂O containing 0.1% TFA (20-100%) as an eluent to provide, afterlyophilization, the title compound (22) (212.4 mg, yield 84%) as a foam.¹H NMR (300 MHz, CDCl₃) δ 9.08 (s, 1H), 8.74 (s, 1H), 6.88 (d, J=7.9 Hz,1H), 4.70-4.51 (m, 2H), 4.23-3.92 (m, 6H), 3.47 (d, J=12.6 Hz, 2H),3.31-3.19 (m, 1H), 2.95 (dd, J=19.6, 11.0 Hz, 3H), 2.34 (dd, J=15.0, 6.2Hz, 1H), 2.10 (s, 2H), 1.91 (ddd, J=15.8, 12.6, 8.0 Hz, 1H), 1.61 (ddd,J=12.5, 8.1, 6.3 Hz, 3H), 1.40-1.16 (m, 14H), 0.91-0.80 (m, 3H). ¹³C NMR(75 MHz, CDCl₃) δ 174.2, 168.6, 167.1, 80.4, 65.5, 61.7, 60.1, 46.6,44.7, 43.3, 42.9, 42.9, 31.4, 31.4, 28.5, 25.6, 25.5, 22.2, 22.2, 21.6,20.7, 17.8, 14.0. ¹⁹F NMR (282 MHz, CDCl₃) δ −75.6. MS (ESI)C₂₃H₄₀N₄O₈S=533 (M+1)⁺. HPLC retention time (MeCN/H₂O in 0.1% TFA): 8.18min.

Example 23 Synthesis of4-((1R,2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium2,2,2-trifluoroacetate (23)

Step 1: Synthesis of heptyl 3-hydroxy-2,2-dimethylpropanoate (23a)

A mixture of 3-hydroxy-2,2-dimethylpropionic acid (4.7 g, 40 mmol),1-heptanol (70 mL) and concentrated sulfuric acid (1 mL) was heated to80° C. and stirred overnight. After allowing to cool, the mixture wasconcentrated under vacuum (high vacuum pump required) and the residuepartitioned between EtOAc (100 mL) and saturated aqueous NaHCO₃ (100mL). The aqueous phase was washed with H₂O (50 mL), saturated NaHCO₃ (50mL) and brine (50 mL), and then dried (Na₂SO₄), filtered andconcentrated under vacuum to provide the product as an oil. The productwas distilled under high vacuum at 65° C. to provide the title compound(23a) as an oil (6.7 g, 77% yield).

¹H NMR (300 MHz, CDCl₃) δ 4.09 (td, J=6.7, 0.9 Hz, 2H), 3.55 (d, J=6.1Hz, 2H), 2.43 (t, J=6.7 Hz, 1H), 1.60 (d, J=22.8 Hz, 4H), 1.3-1.58 (m,6H), 1.27-1.14 (m, 6H), 0.92-0.83 (m, 3H).

Step 2: Synthesis of heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (23b

A solution of sulfuryl chloride (0.6 mL, 7.4 mmol) in Et₂O (15 mL) wascooled to −78° C. under an atmosphere of N₂. A solution of heptyl3-hydroxy-2,2-dimethylpropanoate (23a) (1.0 g, 4.94 mmol) and pyridine(479 μL, 5.93 mmol) in Et₂O (1 mL) was added dropwise to the sulfurylchloride solution over the course of 30 min. The flask was rinsed withEt₂O (3×1 mL) and the rinse added to the reaction mixture. The mixturewas stirred at −78° C. until completion as monitored by TLC (30 min; 30%EA/hexane). The precipitate was filtered, and the filtrate wasconcentrated under vacuum to afford heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (23b) (1.37 g, yield92%). The mixture was stored at −78° C. and used in the next stepwithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 4.50 (s, 2H),4.20-4.02 (m, 2H), 1.68 (m, 2H), 1.31 (d, J=3.1 Hz, 13H), 1.23 (s, 1H),0.95-0.83 (m, 3H).

Step 3: Synthesis of tert-butyl4-((1R,2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(23c)

Hydroxamic acid (1) (2.399 mmol, from hydrogenation, without furtherpurification) was dissolved in THF (12 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (3 mL) and the resultingsolution was cooled to −78° C. under a nitrogen atmosphere. A 1.0 Msolution of NaHMDS in THF (2.4 mL, 2.4 mmol) was added dropwise to thecooled solution and stirred for 20 min. Heptyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (23b) (0.79 g, 2.63 mmol)in THF (5 mL) was rapidly added to the reaction mixture. The syringe wasrinsed with THF (3×2 mL) and the rinse was also added to the mixture.After 10 min, the reaction mixture was warmed to room temperature andstirred until completion as determined by TLC and LC-MS. EtOAc (50 mL)and saturated aqueous NaHCO₃ (50 mL) were added to the mixture. Theaqueous and organic layers were partitioned, and the organic layer waswashed with saturated aqueous NaHCO₃ (10 mL), water (3×10 mL), brine (20mL), and then dried (Na₂SO₄), filtered and concentrated under vacuum toprovide a crude residue. The residue was purified by silica gel columnchromatography using EtOAc/hexane (5% to 95%) as eluent, to give 740.0mg (49% yield) of the product (23c).

Step 4: Synthesis of4-((1R,2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium2,2,2-trifluoroacetate (23)

tert-Butyl4-((1R,2S,5R)-6-(((3-(heptyloxy)-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(23c) (472.1 mg, 0.73 mmol) dissolved in DCM (5 mL) was cooled to −10°C., to which was added TFA (5 mL) dropwise. After completion, thesolvent was evaporated in vacuo and the residue was purified withprep-HPLC using MeCN/H₂O containing 0.1% TFA (20-100%) to give the titlecompound (23) (390 mg, 81% yield) as a solid foam. ¹H NMR (300 MHz,CDCl₃) δ 8.93 (d, J=10.4 Hz, 1H), 8.62 (s, 1H), 6.90 (d, J=7.8 Hz, 1H),4.70-4.51 (m, 2H), 4.18-3.92 (m, 6H), 3.48 (d, J=12.2 Hz, 2H), 3.26 (d,J=11.5 Hz, 1H), 2.98 (dt, J=24.4, 11.7 Hz, 3H), 2.34 (dd, J=15.1, 6.3Hz, 1H), 2.10 (s, 2H), 1.60 (h, J=6.6 Hz, 3H), 1.24 (q, J=11.1, 9.8 Hz,18H), 0.90-0.79 (m, 4H). ¹³C NMR (75 MHz, CDCl₃) δ 174.2, 168.6, 167.1,80.3, 73.9, 65.4, 61.6, 60.1, 46.5, 44.6, 43.4, 42.8, 42.8, 31.6, 28.8,28.4, 28.3, 25.8, 25.7, 22.5, 22.1, 22.1, 21.5, 20.6, 17.8, 14.0. ¹⁹FNMR (282 MHz, CDCl₃) δ −75.7. MS (ESI) C₂₄H₄₂N₄O₈S=547 (M+1)⁺. HPLCretention time (MeCN/H₂O in 0.1% TFA): 9.59 min.

Example 24 Synthesis of4-((1R,2S,5R)-6-(((((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium2,2,2-trifluoroacetate (24)

Step 1: Synthesis of ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (24a)

Diethyl cyclohexane-1,1-dicarboxylate (2.12 g, 9.29 mmol) was dissolvedin THF (50 mL) and to which was added LiAl(OtBu)₃ (5.9 g, 23.2 mmol) inportions. The reaction mixture was stirred at reflux overnight. Thereaction was cooled in an ice bath and treated carefully with 10% KHSO₄aq. solution (30 mL) with stirring for 10 min. The precipitate formedwas filtered out through a pad of Celite®. The filtrate was extractedwith EtOAc (3×40 mL) and the organic phase was combined and washed withbrine (50 mL), dried over NaSO₄, filtered and concentrated in vacuo. Theresidue was purified with CombiFlash (SiO₂) in 0-5% MeOH/DCM to obtainthe desired product (24) as an oil (1.23 g, 71% yield). ¹H NMR (300 MHz,CDCl₃) δ 4.19 (qd, J=7.1, 0.8 Hz, 2H), 3.62 (d, J=6.4 Hz, 2H), 3.46 (s,1H), 2.00 (dt, J=11.5, 6.4 Hz, 4H), 1.57-1.22 (m, 9H).

Step 2: Synthesis of ethyl1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (24b)

A solution of freshly distilled sulfuryl chloride (294 μL, 3.63 mmol) inEt₂O (10 mL) was cooled to −78° C. under an atmosphere of nitrogen. Asolution of ethyl 1-(hydroxymethyl)cyclohexanecarboxylate (24a) (0.615g, 3.3 mmol) and pyridine (294 μL, 3.63 mmol) in Et₂O (6 mL) was addeddropwise to the sulfuryl chloride solution during 15 min. The flask wasrinsed with Et₂O (3×1 mL) and the rinse added to the reaction. Themixture was stirred at −78° C. until completion (ca. 30 min; monitoredby TLC, 30% EtOAc/hexane). The precipitate was filtered, and thefiltrate was concentrated under vacuum to afford the title compound(24b) as an oil, 0.94 g in quantitative yield, which was used directlyin the next step without purification. ¹H-NMR (300 MHz, CDCl₃): δ 4.52(s, 2H), 4.21 (q, J=7.1 Hz, 2H), 2.04 (s, 2H), 1.53-1.39 (m, 8H),1.39-1.21 (m, 3H).

Step 3: Synthesis of tert-Butyl4-((1R,2S,5R)-6-((((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(24c)

Hydroxamic acid (2.73 mmol) was dissolved in THF (14 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (7 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of nitrogen. A 1.0 Msolution of NaHMDS in THF (2.73 mL, 2.73 mmol) was added dropwise over20 min, and the mixture stirred for 10 min. Ethyl1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (24b) (0.94 g, 3.3mmol) in THF (2 mL) was rapidly added to the reaction mixture. After 10min stirring at −78° C., the mixture was allowed to warm to roomtemperature and stirred for 1 h. The reaction mixture was diluted withEtOAc (60 mL) and H₂O at −60° C. The aqueous and organic layers werepartitioned, and the organic layer was washed with H₂O (3×30 mL), andbrine (50 mL), then dried (Na₂SO₄), filtered and concentrated undervacuum to give the crude residue (330 mg). The oil was purified bysilica gel column chromatography using EtOAc/hexane (3:7 to 1:0) aseluent to give the product (24c) (0.98 g, yield 59%) as a solid. ¹H-NMR(300 MHz, CDCl₃): δ 6.43 (d, J=8.2 Hz, 1H), 4.75 (d, J=9.2 Hz, 1H), 4.59(d, J=9.1 Hz, 1H), 4.28-4.05 (m, 5H), 4.04-3.90 (m, 3H), 2.87 (t, J=12.4Hz, 3H), 2.45 (dd, J=15.0, 5.7 Hz, 1H), 2.08-1.84 (m, 4H), 1.56 (d,J=10.6 Hz, 3H), 1.46 (s, 9H), 1.46-1.34 (m, 5H), 1.37-1.20 (m, 8H). MS(ESI) C₂₇H₄₄N₄O₁₀S: 617 (M+H)⁺.

Step 4:4-((1R,2S,5R)-6-((((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidin-1-ium2,2,2-trifluoroacetate (24)

tert-Butyl4-((1R,2S,5R)-6-((((1-(ethoxycarbonyl)cyclohexyl)methoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(24c) (403.3 mg, 0.65 mmol) dissolved in DCM (4 mL) was cooled to −10°C. (salt ice bath) to which was added TFA (4 mL) dropwise. The reactionmonitored by LCMS. After 30 min, it was complete. The solvent wasremoved in vacuo and the residue was purified with prep-HPLC in MeCN/H2Ocontaining 0.1% TFA (20-100%) to give the title compound (24) (263.7 mg,yield 78%) as a solid foam. ¹H NMR (300 MHz, CDCl₃) δ 9.02 (d, J=10.6Hz, 1H), 8.66 (s, 1H), 6.87 (d, J=7.8 Hz, 1H), 4.70 (d, J=9.1 Hz, 1H),4.54 (d, J=9.0 Hz, 1H), 4.16 (dtd, J=12.9, 6.7, 6.3, 3.1 Hz, 4H), 4.00(q, J=8.7, 7.2 Hz, 3H), 3.47 (d, J=12.3 Hz, 2H), 3.26 (d, J=11.5 Hz,1H), 2.95 (dd, J=25.8, 11.9 Hz, 3H), 2.35 (dd, J=15.3, 6.3 Hz, 1H), 2.11(t, J=10.3 Hz, 4H), 1.99 (s, 2H), 2.08-1.87 (m, 2H), 1.89-1.72 (m, 4H),1.54 (d, J=8.0 Hz, 5H), 1.25 (dd, J=14.4, 3.8 Hz, 2H). ¹³C NMR (75 MHz,CDCl₃) δ 173.2, 168.5, 167.0, 80.2, 61.7, 61.1, 60.0, 47.0, 46.6, 44.6,43.3, 30.4, 29.9, 28.3, 25.3, 22.4, 22.2, 22.0, 20.6, 17.7, 14.1. ¹⁹FNMR (282 MHz, CDCl₃) δ −75.7. MS (ESI) C₂₂H₃₆N₄O₈S=517 (M+1)⁺. HPLCretention time (MeCN/H₂O in 0.1% TFA): 8.15 min.

Example 25 Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate(25)

Step 1: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-hydroxy-2,2-dimethylpropanoate (25a)

To a stirred solution of 3-hydroxy-2,2-dimethylpropanoic acid (4.0 g,33.9 mmol) and potassium carbonate (4.68 g, 33.9 mmol) in DMF (45 mL) at0° C. was added 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (5.03 g,33.9 mmol) in DMF (5 mL) dropwise over 1 h. The reaction was stirred atroom temperature overnight. The reaction mixture was diluted with EtOAcand washed with water and brine. The organic layer was dried withanhydrous Na₂SO₄, filtered, and concentrated under vacuum to give acrude residue. The residue was purified by silica gel columnchromatography using EtOAc/hexane (1:4 to 2:3) as eluent to give theproduct (25a) as a yellow liquid (1.6 g, yield 21%). ¹H NMR (300 MHz,CDCl₃): δ 4.86 (s, 2H), 3.58 (s, 2H), 2.18 (s, 3H), 1.20 (s, 6H).

Step 2: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (25b)

A solution of distilled sulfuryl chloride (0.61 mL, 7.53 mmol) in Et₂O(15 mL) was cooled to −78° C. under nitrogen. A solution of(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 3-hydroxy-2,2-dimethylpropanoate(25a) (1.48 g, 6.43 mmol) in Et₂O (1 mL) was added. Subsequently, asolution of pyridine (0.55 mL, 6.86 mmol) in Et₂O (1 mL) was added overa period of 1 h. The reaction was stirred at −78° C. for 1 h. After themixture was filtered, the filtrate was concentrated under vacuum to givethe product (25b) as a yellow oil (1.6 g, yield 76%). ¹H NMR (300 MHz,CDCl₃): δ 4.90 (s, 2H), 4.49 (s, 2H), 2.19 (s, 3H), 1.33 (s, 6H).

Step 3: Synthesis of tert-butyl4-((1R,2S,5R)-6-(((2,2-dimethyl-3-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(25c)

tert-Butyl4-((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(20c) (2.18 mmol) was dissolved in THF (14 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 mL), and the resultingsolution was cooled to −78° C. under nitrogen. A solution of NaHMDS inTHF (1M, 2.62 mL, 2.62 mmol) was added dropwise, and the mixture wasstirred at −78° C. for 10 min. A solution of(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (25b) (106b) (0.86 g,2.62 mmol) in THF (1 mL) was then added to the reaction mixture via asyringe. After stirring for 1 h at −78° C., the reaction mixture wasdiluted with EtOAc and washed with saturated NaHCO₃, water, and brine.The organic layer was dried with anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to give a crude residue. The residue waspurified by silica gel column chromatography using EtOAc/hexane (1:3 to1:1) as eluent to give the product (25c) as a yellow paste (0.44 g,yield 31%). ¹H NMR (300 MHz, CDCl₃): δ 6.73 (d, 1H, J=8.1 Hz), 4.78-4.98(m, 3H), 4.47 (d, 1H, J=8.7 Hz), 3.93-4.15 (m, 5H), 3.27 (d, 1H),2.83-2.92 (m, 3H), 2.41-2.45 (m, 1H), 2.18 (s, 3H), 2.15 (m, 1H),1.78-1.92 (m, 4H), 1.45 (s, 9H), 1.23-1.58 (m, 8H). MS (ESI)C₂₇H₄₀N₄O₁₃S=661 (M+1)⁺.

Step 5: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl2,2-dimethyl-3-(((((1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)propanoate(TFA Salt) (25)

To a solution of tert-butyl4-((1R,2S,5R)-6-(((2,2-dimethyl-3-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(25c) (100 mg, 0.15 mmol) in DCM (3 mL) was added trifluoroacetic acid(0.4 mL) at −10° C. The reaction was stirred at −10° C. for 1 h. LC/MSanalysis indicated that the stating material was consumed. The mixturewas concentrated under vacuum to give a crude residue. The residue waspurified by prep-HPLC on a C18 column eluting using MeCN/H₂O containing0.1% TFA (5-80%) to give the title compound (25) as off-white powder(55.2 mg, yield 55%). ¹H NMR (300 MHz, CDCl₃): δ 9.43 (br s, 1H), 9.05(br s, 1H), 7.14 (d, 1H, J=6.9 Hz), 4.99 (d, 1H, J=13.5 Hz), 4.95 (d,1H, J=8.1 Hz), 4.78 (d, 1H, J=14.1 Hz), 4.41 (d, 1H, J=9.3 Hz), 4.14 (s,1H), 4.06 (m, 1H), 3.98 (d, 1H, J=6.3 Hz), 3.47 (d, 2H), 3.29 (d, 1H),3.04 (m, 2H), 2.86 (d, 1H), 1.82-2.40 (m, 11H), 1.29-1.33 (ds, 6H). ¹³CNMR (75 MHz, CDCl₃): δ 173.9, 169.1, 167.3, 152.9, 141.0, 133.7, 80.3,62.0, 60.4, 54.8, 46.8, 44.7, 43.4, 43.3, 28.5, 22.3, 22.0, 20.8, 18.0,9.6. ¹⁹F NMR (282 MHz, CDCl₃): δ −75.9. MS (ESI) C₂₂H₃₂N₄O₁₁S=561(M+1)⁺.

Analytical HPLC was performed on an Agilent 1200 system using aPhenomenex® C18 column (150×4.6 mm i.d.). The mobile phase was a lineargradient of MeCN and water (0.1% TFA, 5% MeCN to 100% MeCN in 15 min).The flow rate was maintained at 1 mL/min and the eluent was monitoredwith UV detector at 220 nm and 254 nm. HPLC retention time: 7.25 min.

Example 26 Synthesis of(1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-ylhydrogen sulfate (26)

Step 1: Synthesis of tetrabutylammonium(1R,2S,5R)-2-((1-(tert-butoxycarbonyl)piperidin-4-yl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylsulfate (26a)

To a solution of tert-butyl4-((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate(20c) (1.92 g, 5.21 mmol) in DCM (30 mL) was added triethylamine (3 mL)and pyridine-sulfur trioxide complex (3.34 g, 21.0 mmol). The reactionwas stirred at 35° C. overnight. The mixture was concentrated undervacuum to give a crude residue. The residue was stirred with 0.5 Naqueous potassium dihydrogen phosphate solution (30 mL) for 1 h. Theresulting solution was extracted three times with DCM. The combinedorganic layer was dried with anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to give triethylamine salt of(1R,2S,5R)-2-((1-(tert-butoxycarbonyl)piperidin-4-yl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylsulfate (26a) (2.3 g, yield 80%).

To a solution of above product (26a) (2.2 g, 4.0 mmol) in DCM (30 mL)was added 0.5 N aqueous dipotassium hydrogen phosphate (12.4 mL) at 0°C. After stirred at 0° C. for 10 min, tetrabutyl ammonium hydrogensulfate (1.49 g, 4.4 mmol) was added. The resulting solution was stirredat room temperature for 30 min. After the organic layer was separated,the aqueous layer was extracted three times with DCM. The combinedorganic layer was dried with anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to give a residue. The residue was purified bysilica gel column chromatography using 10% MeOH in DCM as eluent to givethe product (26a) (1.35 g, yield 49%) as a white solid. ¹H NMR (300 MHz,CDCl₃): δ 6.55 (d, 1H, J=8.1 Hz), 4.33 (br s, 1H), 4.03 (m, 2H),3.91-3.95 (m, 1H), 3.86 (d, 1H), 3.48 (m, 1H), 3.25-3.31 (m, 10H), 2.85(m, 2H), 2.73 (d, 1H), 2.39 (dd, 1H), 2.13 (m, 1H), 1.81-1.92 (m, 4H),1.60-1.71 (m, 11H), 1.29-1.50 (m, 14H), 1.00 (t, 12H). MS (ESI)C₁₇H₂₈N₄O₈S=446.9 (M−1)⁺.

Step 2: Synthesis of(1R,2S,5R)-7-oxo-2-(piperidin-4-ylcarbamoyl)-1,6-diazabicyclo[3.2.1]octan-6-ylhydrogen Sulfate (26)

To a solution of tetrabutylammonium(1R,2S,5R)-2-((1-(tert-butoxycarbonyl)piperidin-4-yl)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylsulfate (26a) (1.35 g, 1.96 mmol) in DCM (15 mL) at −10° C. was addedTFA (15 mL). After the starting material was consumed as indicated byLC/MS, the mixture was concentrated under vacuum to give a cruderesidue. The residue was stirred with diethyl ether to provide aprecipitate. The solid was filtered, and washed twice with acetone toprovide the title compound (26) as off-white solid (0.56 g, yield 82%).¹H NMR (300 MHz, DMSO-d₆): δ 8.30 (br s, 2H), 8.21 (d, 1H, J=7.5 Hz),3.97 (s, 1H), 3.86 (m, 1H), 3.71 (d, 1H), 3.25 (m, 2H), 2.97 (m, 4H),2.06 (m, 1H), 1.83 (m, 3H), 1.64 (m, 4H). ¹³C NMR (75 MHz, DMSO-d₆):169.5, 166.7, 59.6, 58.0, 46.7, 43.9, 42.5, 28.0, 20.6, 18.6. MS (ESI)C₁₂H₂₀N₄O₆S=346.9 (M+1)⁺. HPLC retention time (MeCN/H₂O in 0.1% TFA):1.60 min.

Example 27 Synthesis of ethyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(27)

Step 1: Synthesis of N-(2-tert-Boc-aminoethoxy)phthalimide (27a)

To a mixture of tert-butyl (2-bromoethyl)carbamate (5.0 g, 22.3 mmol)and N-hydroxyphthalimide (3.64 g, 22.3 mmol) in acetonitrile (80 mL) atroom temperature was added triethylamine (7.46 mL, 53.5 mmol). Thereaction was stirred at 70° C. for 20 h and was then concentrated. Themixture was diluted with ethyl acetate, and washed extensively with 1 NHCl, saturated NaHCO₃, and water. The organic layer was dried withanhydrous Na₂SO₄, filtered, and concentrated under vacuum to give thecrude product (27a) as an off-white solid (3.8 g, yield 56%). ¹H NMR(300 MHz, CDCl₃): δ 7.76-7.87-4.90 (m, 4H), 5.65 (m, 1H), 4.25 (t, 3H),3.44 (t, 3H), 1.46 (s, 9H).

Step 2: Synthesis of tert-butyl (2-(aminooxy)ethyl)carbamate (27b)

To a solution of N-(2-tert-Boc-aminoethoxy)phthalimide (27a) (3.8 g,12.4 mmol) in EtOH (38 mL) at room temperature was added hydrazinemonohydrate (0.63 mL, 13.0 mmol). The reaction was stirred at roomtemperature for 2 h. The mixture was filtered and washed with ethylacetate. The filtrate was concentrated and a white solid was formed. Thewhite solid was removed by filtration and washed with ethyl acetate.This process was repeated three additional times. The combined filtratewas then concentrated to give the product (27b) as a yellow paste (2.16g, yield 99%). ¹H NMR (300 MHz, CDCl₃): δ 5.46 (br s, 2H), 4.91 (br s,1H), 3.70 (m, 2H), 3.35 (m, 2H), 1.44 (s, 9H).

Step 3: Synthesis of tert-butyl(2-(((1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate(27c)

To a mixture of(1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylicacid (20a) (3.19 g, 11.6 mmol), tert-butyl (2-(aminooxy)ethyl)carbamate(27b) (2.06 g, 11.7 mmol) in DCM (20 mL) was added HATU (4.39 g, 11.6mmol) and DIPEA (2.02 mL, 11.6 mmol). The reaction was stirred at roomtemperature overnight. The mixture was washed with saturated NH₄Clsolution, water and brine. The organic layer was dried with anhydrousNa₂SO₄, filtered, and concentrated under vacuum to give a crude residue.The residue was purified by silica gel column chromatography usingEtOAc/hexane (1:1 to 3:1) as an eluent to give the product (27c) as awhite paste (4.0 g, yield 79%). ¹H NMR (300 MHz, CDCl₃): δ 9.46 (br, s,1H), 7.26-7.43 (m, 5H), 5.46 (t, 1H), 4.80-5.10 (dd, 2H, J=11.1 Hz),2.75-3.97 (m, 8H), 1.61-2.33 (m. 4H), 1.43 (t, 9H). MS (ESI)C₂₁H₃₀N₄O₆=435 (M+1)⁺.

Step 4: Synthesis of tert-butyl(2-(((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate(27d)

To a solution of tert-butyl(2-(((1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate(27c) (1.0 g, 2.30 mmol) in MeOH (10 mL) was added 10% palladium oncarbon (0.3 g). The reaction mixture was stirred under 1 atm hydrogenpressure for 1 h. After the mixture was filtered through a pad ofCelite®, the filtrate was concentrated under vacuum to give a crudeproduct (27d) (0.79 g, yield 100%) that was used directly in the nextstep.

Step 5: Synthesis of ethyl3-(((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(27e)

tert-Butyl(2-(((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate(27d) (0.79 g, 2.30 mmol) was dissolved in THF (14 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 mL), and the resultingsolution was cooled to −78° C. under a nitrogen atmosphere. A solutionof NaHMDS in THF (1M, 3.45 mL, 3.45 mmol) was added dropwise, and themixture was stirred at −78° C. for 10 min. A solution of ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (3a) (675 mg, 2.76 mmol)in THF (2 mL) was then added to the reaction mixture via a syringe.After 10 min at −78° C., the reaction mixture was allowed to warm toroom temperature and stirred overnight. The reaction mixture was dilutedwith EtOAc and washed with saturated NaHCO₃, water, and brine. Theorganic layer was dried with anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to give a crude residue. The residue waspurified by silica gel column chromatography using EtOAc/hexane (1:1 to3:1) as eluent to give the product (27e) as an off-white foam (0.68 g,yield 54%). ¹H NMR (300 MHz, CDCl₃): δ 9.60 (br, s, 1H), 5.27 (br, t,1H), 4.58-4.73 (dd, 2H, J=9.3 Hz), 3.02-4.22 (m, 10H), 1.62-2.40 (m.4H), 1.44 (t, 9H), 1.26-1.28 (m, 9H). MS (ESI) C₂₁H₃₆N₄O₁₁S=553 (M+1)⁺.

Step 6: Synthesis of ethyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(27)

To a mixture of ethyl3-(((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(27e) (340 mg, 0.62 mmol) in DCM (4 mL) was added trifluoroacetic acid(4 mL) at −10° C. The reaction mixture was stirred at −10° C. for 30min. LC/MS analysis indicated that the starting material was completelyconsumed. The mixture was concentrated under vacuum to give a cruderesidue. The residue was purified by prep-HPLC on a C18 column elutingwith MeCN/H₂O containing 0.1% TFA (5-80%) to give the title compound(27) as an off-white foam (243 mg, yield 72%). ¹H NMR (300 MHz, CDCl₃):δ 8.10 (br s, 3H), 4.52-4.67 (dd, 2H, J=9.3 Hz), 3.12-4.21 (m, 10H),1.93-2.23 (m, 4H), 1.19-1.29 (m, 9H). ¹³C NMR (75 MHz, CDCl₃): δ 174.7,169.5, 167.6, 80.8, 73.0, 61.7, 60.7, 60.2, 46.5, 43.1, 38.5, 22.3,21.9, 20.6, 18.5, 14.3. ¹⁹F NMR (282 MHz, CDCl₃): δ −75.6. MS (ESI)C₁₆H₂₈N₄O₉S=453 (M+1)⁺.

Analytical HPLC was performed using an Agilent 1200 system with aPhenomenex® C18 column (150×4.6 mm i.d.). The mobile phase was a lineargradient of MeCN and water (0.1% TFA, 5% MeCN to 100% MeCN in 15 min).The flow rate was maintained at 1 mL/min and the eluent was monitoredwith UV detector at 220 nm and at 254 nm. HPLC retention time: 7.10 min.

Example 28 Synthesis of 2-methoxyethyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(28)

Step 1: Synthesis of 2-methoxyethyl3-(((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(28a)

tert-butyl(2-(((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate(27d) (0.79 g, 2.30 mmol) was dissolved in THF (14 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (6 mL), and the resultingsolution was cooled to −78° C. under a nitrogen atmosphere. A solutionof NaHMDS in THF (1M, 2.76 mL, 2.76 mmol) was added dropwise, and themixture was stirred at −78° C. for 10 min. A solution of 2-methoxyethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (15b) (758 mg, 2.76 mmol)in THF (2 mL) was then added to the reaction mixture via a syringe.After 10 min at −78° C., the reaction mixture was allowed to warm toroom temperature and stirred overnight. The reaction mixture was dilutedwith EtOAc and washed with saturated NaHCO₃, water, and brine. Theorganic layer was dried with anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to give a crude residue. The residue waspurified by silica gel column chromatography using EtOAc/hexane (1:1 to3:1) as eluent to give the product (28a) as a white foam (0.65 g, yield49%). ¹H NMR (300 MHz, CDCl₃): δ 9.60 (br, s, 1H), 5.30 (br, t, 1H),4.60-4.72 (dd, 2H, J=8.7 Hz), 3.02-4.22 (m, 15H), 1.62-2.40 (m. 4H),1.45 (t, 9H), 1.21-1.30 (m, 6H). MS (ESI) C₂₂H₃₈N₄O₁₂S=583 (M+1)⁺.

Step 2: Synthesis of 2-methoxyethyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(28)

To a mixture of 2-methoxyethyl3-(((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(28a) (0.33 g, 0.57 mmol) in DCM (4 mL) was added trifluoroacetic acid(4 mL) at −10° C. The reaction was stirred at −10° C. for 30 min. LC/MSanalysis indicated that the stating material was completely consumed.The mixture was concentrated under vacuum to give a crude residue. Theresidue was purified by prep-HPLC on a C18 column eluting using MeCN/H₂Ocontaining 0.1% TFA (5-80%) to give the title compound (28) as off-whitefoam (128 mg, yield 39%). ¹H NMR (300 MHz, CDCl₃): δ 8.10 (br s, 3H),4.53-4.68 (dd, 2H, J=8.7 Hz), 3.11-4.21 (m, 15H), 1.96-2.23 (m, 4H),1.28 (s, 6H). ¹³C NMR (75 MHz, CDCl₃): δ 174.6, 169.5, 167.6, 80.6,72.9, 70.6, 64.5, 60.6, 60.1, 59.2, 46.5, 43.2, 38.4, 22.2, 21.9, 20.5,18.5. ¹⁹F NMR (282 MHz, CDCl₃): δ 75.6. MS (ESI) C₁₇H₃₀N₄O₁₀S=483(M+1)⁺. HPLC retention time (MeCN/H₂O in 0.1% TFA): 6.59 min.

Example 29 Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoateTFA Salt (29)

Step 1: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-(((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(29a)

tert-Butyl(2-(((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate(27d) (0.80 g, 2.32 mmol) was dissolved in THF (23 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (3.3 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of nitrogen. Asolution of NaHMDS in THF (1M, 2.32 mL, 2.32 mmol) was added dropwise,and the mixture was stirred at −78° C. for 10 min. A solution of(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (25b) (916 mg, 2.8 mmol)in THF (2 mL) was then added to the reaction mixture via a syringe.After 10 min at −78° C., the reaction mixture was allowed to warm toroom temperature and stirred overnight. The reaction mixture was dilutedwith EtOAc and washed with water, and brine. The organic layer was driedwith anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give acrude residue. The residue was purified by silica gel columnchromatography using EtOAc/hexane (0-99%) as eluent to give the product(29a) as off-white foam (399.8 mg, yield 27%). ¹H NMR (300 MHz,chloroform-d) δ 9.75 (s, 1H), 5.37 (s, 1H), 5.30 (d, J=0.7 Hz, 2H),5.00-4.76 (m, 2H), 4.46 (d, J=9.3 Hz, 1H), 4.16-4.00 (m, 2H), 3.94 (s,4H), 3.42 (s, 2H), 3.38-3.26 (m, 4H), 3.03 (d, J=12.2 Hz, 2H), 2.19 (s,6H), 2.16 (d, J=5.5 Hz, 2H), 2.02 (d, J=14.0 Hz, 3H), 1.92 (s, 2H), 1.56(m, 1H), 1.48-1.41 (m, 9H), 1.41-1.20 (m, 6H). MS (ESI) C₂₄H₃₆N₄O₁₄S:637 (M+1)⁺.

Step 2: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoateTFA Salt (29)

To a mixture of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-(((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(29a) (0.33 g, 0.52 mmol) in DCM (3 mL) was added trifluoroacetic acid(0.3 mL) at −10° C. The reaction was stirred at −10° C. for 4 h. LC/MSanalysis indicated that the stating material was completely consumed.The mixture was concentrated under vacuum to give a crude residue. Theresidue was purified by prep-HPLC on C18 column eluting using MeCN/H₂Ocontaining 0.1% TFA (0-80%) to give the title compound (29) as off-whitefoam (9.1 mg, yield 3.2%). ¹H NMR (300 MHz, MeCN-d₃): δ 7.61 (s, 1H),4.97-4.83 (m, 3H), 4.74-4.60 (m, 1H), 4.55 (d, J=9.3 Hz, 1H), 4.24-4.00(m, 2H), 3.94-3.83 (m, 1H), 3.73-3.62 (m, 2H), 3.29 (d, J=12.3 Hz, 2H),3.19 (s, 3H), 2.15 (dq, J=1.3, 0.6 Hz, 3H), 1.93 (s, 1H), 1.39-1.07 (m,8H). ¹⁹F NMR (282 MHz, MeCN-d₃): δ −76.1, −76.3. MS (ESI) C₁₉H₂₈N₄O₁₂S:537 (M+1)⁺

Example 30 Synthesis of hexyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyloxy)-2,2-dimethylpropanoateTFA Salt (30)

Step 1: Synthesis of hexyl3-(((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(30a)

tert-Butyl(2-(((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate(27d) (0.51 g, 1.48 mmol) was dissolved in THF (18 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (2.8 mL), and the resultingsolution was cooled to −78° C. under a nitrogen atmosphere. A solutionof NaHMDS in THF (1M, 1.9 mL, 1.9 mmol) was added dropwise, and themixture was stirred at −78° C. for 10 min. A solution of hexyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (730 mg, 2.42 mmol) inTHF (2 mL) was then added to the reaction mixture via a syringe. After10 min at −78° C., the reaction mixture was allowed to warm to roomtemperature and stirred overnight. The reaction mixture was diluted withEtOAc and washed with water, and brine. The organic layer was dried withanhydrous Na₂SO₄, filtered, and concentrated under vacuum to give acrude residue. The residue was purified by silica gel columnchromatography using EtOAc/hexane (0-99%) as eluent to give the product(30a) as off-white foam (194.3 mg, yield 22%). ¹H NMR (300 MHz, CDCl₃):δ 9.54 (s, 1H), 5.26 (s, 1H), 4.60 (d, J=9.0 Hz, 2H), 4.21-4.02 (m, 7H),3.46 (d, J=16.3 Hz, 1H), 3.31 (s, 2H), 3.03 (d, J=12.0 Hz, 1H), 2.39(dd, J=14.9, 6.3 Hz, 1H), 2.19 (s, 1H), 2.08-1.89 (m, 2H), 1.65-1.55 (m,2H), 1.45 (s, 10H), 1.35-1.19 (m, 10H), 0.94-0.79 (m, 3H). MS (ESI)C₂₅H₄₄N₄O₁₁S: 607 (M−1)⁺.

Step 2: Synthesis of hexyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoateTFA Salt (30)

To a solution of hexyl3-(((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(30a) (144.3 mg, 0.237 mmol) in DCM (3 mL) was added trifluoroaceticacid (0.15 mL) at 0° C. The reaction was stirred at 0° C. for 1 h. LC/MSanalysis indicated that the stating material was completely consumed.The mixture was concentrated under vacuum to give a crude residue. Theresidue was purified by prep-HPLC on a C18 column eluting using MeCN/H₂Ocontaining 0.1% TFA (0-80%) to give the title compound (30) as a brownoil (68.1 mg, yield 56%). ¹H NMR (300 MHz, CDCl₃): δ 7.80-7.73 (m, 2H),6.94 (s, 1H), 4.57 (dt, J=28.2, 14.1 Hz, 2H), 4.22 (s, 1H), 4.08 (ddt,J=17.3, 13.2, 8.0 Hz, 6H), 3.96 (s, 2H), 3.28 (d, J=10.2 Hz, 2H), 2.10(s, 1H), 1.93 (s, 1H), 1.62 (m, 2H), 1.28 (ddd, J=12.8, 6.5, 3.7 Hz,12H), 1.19 (s, 2H), 0.94-0.82 (m, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 176.6,174.3, 169.2, 167.3, 161.6, 118.2, 114.3, 80.4, 73.7, 72.6, 65.5, 65.3,60.3, 59.9, 46.3, 42.9, 42.8, 38.4, 31.4, 28.4, 28.3, 25.5, 25.5, 22.5,22.1, 22.0, 21.6, 20.3, 18.2, 14.0. ¹⁹F NMR (282 MHz, CDCl₃): δ −75.8.MS (ESI) C₂₀H₃₆N₄O₉S: 509 (M+1)⁺. HPLC retention time (MeCN/H₂O in 0.1%TFA): 8.96 min.

Example 31 Synthesis of heptyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoateTFA Salt (31)

Step 1: Synthesis of heptyl3-(((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(31a)

A method similar to that of Step 1 of Example 30 was used to obtain274.0 mg of the title compound (31a) (44% yield) as off white solid. ¹HNMR (300 MHz, CDCl₃): δ 9.75 (s, 1H), 5.37 (t, J=6.2 Hz, 1H), 4.72-4.52(m, 2H), 4.09 (dddd, J=18.6, 10.4, 3.8, 2.1 Hz, 3H), 3.91 (t, J=4.8 Hz,2H), 3.51-3.19 (m, 3H), 3.05 (d, J=12.1 Hz, 1H), 2.43-2.29 (m, 1H),2.21-2.07 (m, 1H), 2.06-1.77 (m, 3H), 1.62 (t, J=6.9 Hz, 2H), 1.40 (s,9H), 1.40-1.17 (m, 16H), 0.92-0.81 (m, 3H). MS (ESI) C₂₆H₄₆N₄O₁₁S: 523(M+1-Boc)⁺.

Step 2: Synthesis of heptyl3-(((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoateTFA Salt (31)

A method similar to that of Step 2 of Example 30 was used to prepare thetitle compound (31) (214.5 mg, 93%) as a brown oil. ¹H NMR (300 MHz,CDCl₃): δ 10.61 (s, 1H), 8.02 (s, 3H), 4.63 (d, J=8.7 Hz, 1H), 4.53 (d,J=8.9 Hz, 1H), 4.17 (d, J=13.3 Hz, 3H), 4.12-3.97 (m, 4H), 3.95 (s, 1H),3.26 (s, 3H), 3.18-3.08 (m, 1H), 2.22 (s, 1H), 2.10 (s, 1H), 1.61 (q,J=7.0 Hz, 2H), 1.25 (m, 12H), 1.18 (s, 2H), 0.87 (m, 3H). ¹³C NMR (75MHz, CDCl₃): δ 176.5, 174.3, 169.1, 167.3, 80.3, 73.7, 72.6, 65.5, 65.3,60.3, 59.9, 46.3, 42.9, 42.8, 38.3, 31.7, 31.7, 28.9, 28.9, 28.4, 25.8,25.8, 22.6, 22.1, 22.0, 22.0, 21.6, 20.3, 18.3, 14.0. ¹⁹F NMR (282 MHz,CDCl₃): δ −75.71. MS (ESI) C₂₁H₃₈N₄O₉S: 523 (M+1)⁺. HPLC retention time(MeCN/H₂O in 0.1% TFA): 9.37 min.

Example 32 Synthesis of ethyl1-((((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylateTFA Salt (32)

Step 1: Synthesis of ethyl1-((((((1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate(32a)

A method similar to that of Step 1 of Example 30 was applied for thecoupling between tert-butyl(2-(((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamateand ethyl 1-(((chlorosulfonyl)oxy)methyl)cyclohexanecarboxylate (27d) togive 122.2 mg of the title compound (32a) (14% yield for 3 steps as) offwhite solid. ¹H NMR (300 MHz, CDCl₃): δ 9.92 (d, J=5.6 Hz, 1H), 5.46 (d,J=5.7 Hz, 1H), 4.68 (d, J=9.2 Hz, 1H), 4.52 (d, J=9.2 Hz, 1H), 4.24-3.98(m, 5H), 3.88 (t, J=4.8 Hz, 2H), 3.37 (d, J=6.7 Hz, 1H), 3.25 (dt,J=10.1, 5.1 Hz, 2H), 3.04 (d, J=12.1 Hz, 1H), 2.30 (t, J=6.8 Hz, 1H),2.16-1.80 (m, 6H), 1.52 (d, J=9.3 Hz, 3H), 1.4 (s, 9H), 1.34 (m, 2H),1.22 (td, J=7.2, 5.0 Hz, 3H). MS (ESI) C₂₄H₄₀N₄O₁₁S: 593 (M+1)⁺.

Step 2: Synthesis of ethyl1-((((((1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylateTFA Salt (32)

A method similar to that of Step 2 of Example 30 was applied to obtain91.4 mg of the title compound (32) (90% yield) as off white solid. ¹HNMR (300 MHz, CDCl₃): δ 10.74 (s, 1H), 7.98 (s, 3H), 4.65 (d, J=9.2 Hz,1H), 4.50 (d, J=9.1 Hz, 1H), 4.26-4.04 (m, 3H), 4.13 (s, 3H), 3.95 (s,1H), 3.26 (d, J=9.9 Hz, 3H), 3.14 (d, J=11.6 Hz, 1H), 2.02 (s, 4H), 1.92(s, 3H), 1.50-1.22 (m, 8H), 1.22 (d, J=7.5 Hz, 2H). ¹³C NMR (75 MHz,CDCl₃): δ 175.6, 173.5, 169.2, 167.3, 118.5, 114.6, 80.3, 73.6, 72.6,61.3, 61.1, 60.3, 60.0, 47.2, 47.1, 46.2, 38.2, 30.6, 30.2, 30.1, 25.5,25.3, 22.4, 22.1, 22.0, 20.3, 18.3, 14.1. ¹⁹F NMR (282 MHz, CDCl₃): δ−75.7. MS (ESI) C₁₉H₃₂N₄O₉S: 493 (M+1)⁺. HPLC retention time (MeCN/H₂Oin 0.1% TFA): 8.05 min.

Example 33 Synthesis of(1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylhydrogen Sulfate (33)

Step 1: Synthesis of tetrabutylammonium(1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylsulfate (33a)

To a solution of tert-butyl(2-(((1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)carbamate(27d) (0.79 g, 2.30 mmol) in pyridine (35 mL) was added pyridine-sulfurtrioxide complex (1.46 g, 9.2 mmol). The reaction was stirred at roomtemperature for 64 h. Additional pyridine-sulfur trioxide complex (1.46g, 9.2 mmol) was added and the reaction was stirred at 35° C. for 16 h.The mixture was concentrated under vacuum to give a crude residue. To asolution of above product in DCM (30 mL) was added 0.5 N aqueousdipotassium hydrogen phosphate (7.4 mL) at 0° C. After stirred at 0° C.for 10 min, tetrabutyl ammonium hydrogen sulfate (0.86 g, 2.53 mmol) wasadded. The resulting solution was stirred at room temperature for 30min. After the organic layer was separated, the aqueous layer wasextracted three times with DCM. The combined extracted organic layerswere dried with anhydrous Na₂SO₄, filtered, and concentrated undervacuum to give a residue. The residue was purified by silica gel columnchromatography using 10% MeOH in DCM as eluent to give the product (33a)as an off-white solid (0.51 g, yield 33%). MS (ESI) C₁₄H₂₄N₄O₉S=423(M−1)⁺.

Step 2: Synthesis of(1R,2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylhydrogen Sulfate (33)

To a solution of tetrabutylammonium(1R,2S,5R)-2-((2-((tert-butoxycarbonyl)amino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylsulfate (33a) (0.51 g, 0.77 mmol) in DCM (10 mL) at −10° C. was addedTFA (10 mL). LC/MS analysis indicated that the reaction was completeafter 1 h. The mixture was concentrated under vacuum to give a cruderesidue. The residue was stirred with diethyl ether to provide a yellowprecipitate. The solid was filtered, and washed with acetone. Theresidue was dissolved in water and acetonitrile (1:1) and lyophilized toprovide a yellow solid. The residue was washed with acetone again. Theresidue was dissolved in water and acetonitrile (1:1) and lyophilized toprovide the title compound (33) as a yellow solid (68 mg, yield 27%). ¹HNMR (300 MHz, DMSO-d₆): δ 7.84 (br s, 3H), 3.82-4.00 (m, 3H), 2.92-3.33(m, 5H), 2.00 (m, 1H), 1.87 (m, 1H), 1.68 (m, 2H). ¹³C NMR (75 MHz,DMSO-d₆): 169.1, 166.5, 72.8, 58.6, 58.3, 47.7, 38.2, 21.3, 19.0. MS(ESI) C₉H₁₆N₄O₇S=323 (M−1)⁺. HPLC retention time (MeCN/H₂O in 0.1% TFA):1.52 min.

Example 34 Synthesis of(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl1H-imidazole-1-sulfonate (34)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (741 mg, 4.0 mmol) was dissolved in tetrahydrofuran (36 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (2 mL), and the resultingsolution was cooled to −78° C. A solution of NaHMDS, 1.0M in THF (4.4mL, 4.4 mmol) was added dropwise to the cooled solution and stirred for10 min. 1-((1H-Imidazol-1-yl)sulfonyl)-3-methyl-1H-imidazol-3-iumtrifluoromethanesulfonate (prepared according to Org. Lett. 2013, 15,18-21 & J. Org. Chem. 2003, 68, 115-119) (2.90 g, 8.0 mmol) was addedquickly to the reaction mixture. After 10 min, the reaction mixture waswarmed to 0° C. (reaction monitored by TLC using 70% EtOAc/hexanes). Themixture was stirred for 1 h at room temperature, then diluted with EtOAc(50 mL) and quenched with saturated aqueous NaHCO₃ (50 mL). The organicand aqueous layers were separated, and the organic layer washed withsaturated aqueous NaHCO₃ (50 mL), H₂O (3×50 mL), and brine (50 mL), andthen dried (Na₂SO₄), and concentrated under vacuum to leave a cruderesidue. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (1:9 to 1:0) as eluent to give the product (34)(0.393 g, 31%) as a solid. LC-MS: m/z=316.0 [M+H]⁺. ¹H NMR (300 MHz,1,4-dioxane-d₈): δ 8.15 (s, 1H), 7.58 (ft, J=1.5 Hz, 1H), 7.15 (s, 1H),6.92 (s, 1H), 6.48 (s, 1H), 3.95 (d, J=6.3 Hz, 1H), 3.70 (s, 1H), 3.08(s, 2H), 2.23-2.17 (m, 1H), 2.04-1.97 (m, 1H), 1.88-1.74 (m, 2H). ¹³CNMR (75 MHz, 1,4-dioxane-d₈): δ 171.4, 167.6, 139.2, 132.0, 119.9, 62.9,61.8, 46.9, 21.5, 18.7.

Example 35 Synthesis of ethyl5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.11]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate(35)

Step 1: Synthesis of ethyl 5-hydroxy-4,4-dimethylpentanoate (35a)

To a suspension of sodium 5-ethoxy-2,2-dimethyl-5-oxopentanoate (3.77 g,17.9 mmol) in a mixture of tetrahydrofuran (39 mL) and DMF (13 mL) wasadded a solution of isopropyl chloroformate, 1.0M in toluene (27.0 mL,27.0 mmol) at 0° C. The mixture was stirred at 0° C. for 10 min, andthen allowed to warm to room temperature, and stirred for 2 h. Thesolution was cooled to 0° C. and sodium borohydride (1.21 g, 35.9 mmol)was added. The mixture was stirred for 20 min then methanol (6.5 mL) wasadded to the solution. After 10 min of stirring, ethyl acetate (25 mL)modified with a few drops of triethylamine and a saturated aqueoussolution of NH₄Cl (25 mL) were added. The layers were separated, and theaqueous layer was extracted with EtOAc (2×40 mL). The combined organiclayers were washed with brine, dried (MgSO₄), filtered and the filtratewas concentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes modified with 0.1% TEA(5:95 to 4:6) to give the product (35a) (2.01 g, 64% crude) as acolorless oil. One drop of triethylamine was added to the product tosuppress lactonization.

Step 2: Synthesis of ethyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (35b)

A solution of sulfuryl chloride (0.64 mL, 8.7 mmol) in Et₂O (10 mL) wascooled to −78° C. under an atmosphere of nitrogen. A solution of ethyl5-hydroxy-4,4-dimethylpentanoate (35a) (0.76 g, 4.4 mmol) and pyridine(0.39 mL, 4.8 mmol) in Et₂O (10 mL) was added dropwise to the sulfurylchloride solution over the course of 10 min. The syringe was rinsed withEt₂O (3×1 mL) and this was also added to the mixture. The mixture wasstirred at −78° C. for 1.5 h, additional pyridine (0.9 equiv.) wasadded, and the mixture was filtered through a pad of Celite®. Thefiltrate was concentrated under vacuum to give the product (35b) (0.897g) as a colorless oil. This was used in the next step without furtherpurification.

Step 3: Synthesis of ethyl5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate(35)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (278 mg, 1.5 mmol) was dissolved in THF (14 mL) and HMPA (0.6 mL),and the resulting solution was cooled to −78° C. under a nitrogenatmosphere. A solution of ethyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (35b) (0.45 g, 1.6 mmol)in THF (3 mL) was cooled to −78° C. and quickly added to the mixture.The flask containing the sulfating reagent was rinsed with THF (1 mL),while the flask temperature was maintained at −78° C., and this wasadded quickly to the reaction mixture. After stirring for 15 min, themixture was warmed to room temperature and stirred for 45 min. Themixture was diluted with EtOAc (30 mL) and the reaction quenched withsaturated aqueous NaHCO₃ (30 mL). The organic and aqueous layers werepartitioned, and the organic layer was washed with water (3×30 mL), andbrine (30 mL), dried (MgSO₄), and the solvent removed under vacuum. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (3:7 to 4:1) to give the product (35) (157 mg, 25%) as asolid. LC-MS: m/z=422.2 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 5.52 (s, 1H),5.83 (s, 1H), 4.49 (d, J=9.3 Hz, 1H), 4.21-4.08 (m, 4H), 4.03 (d, J=6.9Hz, 1H), 3.34-3.30 (m, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.43-2.38 (m, 1H),2.32-2.26 (m, 2H), 2.17-2.11 (m, 1H), 1.99-1.82 (m, 2H), 1.72-1.66 (m,3H), 1.25 (t, J=7.1 Hz, 3H), 0.98 (s, 6H). ¹³C NMR (75 MHz, CDCl₃):δ173.5, 171.1, 167.1, 83.4, 62.0, 60.6, 60.3, 47.2, 34.2, 33.3, 29.3,23.6, 23.3, 20.8, 17.6, 14.3.

Example 36 Synthesis of hexyl5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate(36)

Step 1: Synthesis of sodium-5-(hexyloxy)-2,2-dimethyl-5-oxopentanoate(36a)

To a solution of 2,2-dimethylglutaric anhydride (5.0 g, 35.2 mmol) in1-hexanol (50 mL) was added a solution of sodium hexan-1-olate (5.4 g,43.5 mmol) in 1-hexanol. After 20 h of stirring, the solvent wasevaporated and the resulting solid was suspended in diethyl ether (80mL). The mixture was filtered and the solid was washed with diethylether (2×40 mL). The solid was dried under high vacuum to afford theproduct (36a) (3.84 g, 41%) as a solid. ¹H NMR (300 MHz, D₂O): δ 4.14(t, J=6.5 Hz, 2H), 2.38-2.33 (m, 2H), 1.82-1.77 (m, 2H), 1.75-1.63 (m,2H), 1.43-1.28 (m, 6H), 1.12 (s, 6H), 0.92-0.88 (m, 3H). The spectrumrevealed that the product was contaminated with a small amount of anunidentified substance.

Step 2: Synthesis of hexyl 5-hydroxy-4,4-dimethylpentanoate (36b)

To a suspension of sodium 5-(hexyloxy)-2,2-dimethyl-5-oxopentanoate(36a) (3.84 g, 14.4 mmol) in a mixture of THF (31 mL) and DMF (10 mL)was added isopropyl chloroformate, 1.0M in toluene (21.6 mL, 21.6 mmol)at 0° C. and the mixture was stirred for 10 min. After 3.3 h of stirringat room temperature, the solution was cooled to 0° C. and sodiumborohydride (0.98 g, 28.8 mmol) was added. The mixture was stirred for20 min and MeOH (5.2 mL) was added to the solution (reaction monitoredby TLC using 2:8 ethyl acetate/hexanes as eluent). After 15 min, a fewdrops of triethylamine were added. After another 15 min of stirring,ethyl acetate (25 mL) and a solution of saturated aqueous NH₄Cl wasadded (25 mL). The organic and aqueous layers were separated, and theaqueous layer was extracted with EtOAc (2×40 mL). The combined organiclayers were washed with brine, dried (MgSO₄), and filtered, and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes modified with 0.1% Et₃N(5:95 to 3:7) to give the product (36b) (2.16 g, 65%) as a colorlessoil. One drop of Et₃N was added to suppress lactonization.

Step 3: Synthesis of hexyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (36c)

A solution of sulfuryl chloride (0.38 mL, 5.2 mmol) in Et₂O (8.5 mL) wascooled to −78° C. under a nitrogen atmosphere. A solution of hexyl5-hydroxy-4,4-dimethylpentanoate (36b) (0.60 g, 2.6 mmol) and pyridine(0.42 mL, 5.2 mmol) in Et₂O (8.5 mL) was added dropwise to the sulfurylchloride solution over the course of 10 min. The syringe was rinsed withEt₂O (3×1 mL) and the rinse was also added to the mixture. The mixturewas stirred for 4.5 h (reaction monitored by TLC using 2:8 EtOAc/hexanesas eluent). The solids were filtered off and the solvent wasconcentrated in vacuo to give the product (36c) as a colorless oil witha quantitative yield. To this was added 3 mL of THF and the solution wasstored at −78° C. This was used in the next step without furtherpurification.

Step 4: Synthesis of hexyl5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate(36)

(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (370 mg, 2.0 mmol) was dissolved in tetrahydrofuran (19 mL) and HMPA(0.8 mL), and the resulting solution was cooled to −78° C. under anatmosphere. A solution of NaHMDS, 1.0 M in THF (2.2 mL, 2.2 mmol) wasadded dropwise to the cooled solution and stirred for 10 min. A solutionof hexyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (36c) (0.72 g,2.2 mmol) in THF (3 mL) was cooled to −78° C. and quickly added to thereaction mixture. The flask containing the sulfating reagent was rinsedwith THF (3×1 mL), while the flask temperature was maintained at −78°C., and the rinse was quickly added to the reaction mixture. Afterstirring for 10 min the mixture was warmed to room temperature andstirred overnight. The reaction was then quenched with saturated NaHCO₃(40 mL) and extracted with EtOAc (40 mL). The organic layer wasconcentrated, and the oily residue partitioned between H₂O (40 mL) andEtOAc (40 mL). The organic layer was washed with brine, dried (MgSO₄),filtered and concentrated under vacuum. The residue was purified bycolumn chromatography on silica gel using EtOAc/hexanes as eluent (1:9to 8:2) to give the product (36) (421 mg, 44%) as a solid. LC-MS:m/z=478.0 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 6.48 (s, 1H), 5.59 (s, 1H),4.51 (d, J=8.7 Hz, 1H), 4.22-4.18 (m, 2H), 4.08-4.04 (m, 3H), 3.36-3.32(m, 1H), 3.02 (d, J=12.6 Hz, 1H), 2.47-2.41 (m, 1H), 2.33-2.28 (m, 2H),2.18-2.13 (m, 1H), 2.01-1.79 (m, 2H), 1.72-1.59 (m, 4H), 1.35-1.31 (m,6H), 0.99 (s, 6H), 0.91-0.87 (m, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 173.6,170.9, 167.1, 83.5, 64.9, 62.0, 60.2, 47.3, 34.3, 33.3, 31.6, 29.3,28.7, 25.7, 23.6, 23.3, 22.7, 20.9, 17.6, 14.1.

Example 37 Synthesis of heptyl5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate(37)

Step 1: Synthesis of sodium 5-(heptyloxy)-2,2-dimethyl-5-oxopentanoate(37a)

To a solution of 2,2-dimethylglutaric anhydride (5.0 g, 35.2 mmol) in1-heptanol (40 mL) was added a solution of sodium heptan-1-olate (6.01g, 43.5 mmol) in 1-heptanol (30 mL). After stirring overnight thesolvent was evaporated and the resulting solid was suspended in Et₂O (80mL). The mixture was filtered and the solid was washed with Et₂O (2×40mL). The solid was dried under high vacuum to afford the product (37a)(7.89 g, 80%) as a solid. ¹H NMR (300 MHz, D₂O): δ 4.14 (t, J=6.5 Hz,2H), 2.36-2.32 (m, 2H), 1.82-1.77 (m, 2H), 1.74-1.63 (m, 2H), 1.40-1.31(m, 8H), 1.11 (s, 6H), 0.92-0.87 (m, 3H). The spectrum revealed that theproduct was contaminated with a small amount of an unidentifiedsubstance.

Step 2: Synthesis of heptyl 5-hydroxy-4,4-dimethylpentanoate (37b)

To a suspension of sodium 5-(heptyloxy)-2,2-dimethyl-5-oxopentanoate(37a) (7.89 g, 28.1 mmol) in a mixture of THF (61 mL) and DMF (20 mL)was added isopropyl chloroformate, 1.0M in toluene (42.2 mL, 42.2 mmol)at 0° C. and the mixture was stirred for 10 min. After 4 h of stirringat room temperature, the suspension was cooled to 0° C. and sodiumborohydride (1.9 g, 56.3 mmol) was added. The mixture was stirred for 20min and then MeOH (10 mL) was added to the solution (reaction monitoredby TLC using 2:8 ethyl acetate/hexanes). After 30 min of stirring, EtOAc(50 mL), a few drops of Et₃N, and a saturated aqueous solution of NH₄Clwere added (50 mL). The aqueous and organic layers were separated, andthe aqueous layer was extracted with EtOAc (2×80 mL). The combinedorganic layers were washed with brine (80 mL), and the filtrate wasconcentrated in vacuo. The residual solution was washed with H₂O (3×100mL), brine (100 mL), and dried (Na₂SO₄), and concentrated. During allextractions, several drops of Et₃N were added to the organic layer tosuppress lactonization. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes modified with 0.1% Et₃N(0:1 to 3:7) as eluent to give the product (37b) (3.35 g, 49% crude) asa colorless oil.

Step 3: Synthesis of heptyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (37c)

A solution of sulfuryl chloride (0.60 mL, 8.2 mmol) in Et₂O (13 mL) wascooled to −78° C. under a nitrogen atmosphere. A solution of heptyl5-hydroxy-4,4-dimethylpentanoate (37b) (1.0 g, 4.1 mmol) and pyridine(0.66 mL, 8.2 mmol) in Et₂O (13 mL) was added dropwise to the sulfurylchloride solution over the course of 10 min. The syringe was rinsed withdiethyl ether (3×1 mL) and this was also added to the mixture. Themixture was stirred for 4.5 h (reaction monitored by TLC using 2:8 ethylacetate/hexanes as eluent). The solids were filtered-off, and thefiltrate concentrated in vacuo to give the product (37c) (1.13 g) as acolorless oil. To this was added 3 mL of THF and the solution stored at−78° C. This was used in the next step without further purification.

Step 4: Synthesis of heptyl5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)sulfonyl)oxy-4,4-dimethylpentanoate (37)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.56 g, 3.0 mmol) was dissolved in THF (28 mL) and HMPA (1.2 mL),and the resulting solution was cooled to −78° C. under an atmosphere ofnitrogen. A solution of NaHMDS, 1.0 M in THF (3.3 mL, 3.3 mmol) wasadded dropwise to the cooled solution and stirred for 10 min. A solutionof heptyl 5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (37c) (1.13 g,3.3 mmol) was dissolved in THF (3 mL, with the temperature maintained at−78° C.) and quickly added to the reaction mixture. The flask containingthe sulfating reagent was rinsed with THF (3×1 mL), while the flasktemperature was maintained at −78° C., and this was also added quicklyto the reaction mixture. After stirring for 10 min, the mixture waswarmed to room temperature and stirred overnight. The mixture wasquenched with a saturated aqueous solution of sodium bicarbonate (60 mL)and extracted with EtOAc (60 mL). The organic layer was concentrated,and the oily residue diluted with EtOAc (60 mL) and washed with water(2×60 mL). The organic layer was washed with brine, dried (MgSO₄), andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel EtOAc/hexanes (1:9 to 8:2) as eluent togive the product (37) (473 mg, 32%) as a solid. LC-MS: m/z=492.0 [M+H]⁺.¹H NMR (300 MHz, CDCl₃): δ 6.48 (s, 1H), 5.62 (s, 1H), 4.51 (d, J=9.3Hz, 1H), 4.22-4.18 (m, 2H), 4.08-4.04 (m, 3H), 3.36-3.31 (m, 1H), 3.02(d, J=12.6 Hz, 1H), 2.47-2.41 (m, 1H), 2.33-2.28 (m, 2H), 2.18-2.13 (m,1H), 2.01-1.80 (m, 2H), 1.72-1.60 (m, 4H), 1.31-1.28 (m, 8H), 0.99 (s,6H), 0.91-0.86 (m, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 173.6, 170.9, 167.1,83.4, 64.9, 62.0, 60.2, 47.2, 34.2, 33.3, 31.8, 29.2, 29.0, 28.7, 26.0,23.6, 23.3, 22.7, 20.8, 17.6, 14.2.

Example 38 Synthesis of 2-methoxyethyl5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate(38)

Step 1: Synthesis of sodium5-(2-methoxyethoxy)-2,2-dimethyl-5-oxopentanoate (38a)

To a solution of 2,2-dimethylglutaric anhydride (5.0 g, 35.2 mmol) in2-methoxyethanol (30 mL) was added a solution sodium 2-methoxyethanolate(4.27 g, 43.5 mmol) in 2-methoxyethanol (30 mL). After 20 h of stirring,the solvent was evaporated and the resulting solid was suspended in Et₂O(80 mL). The mixture was filtered and the solid was washed with Et₂O(2×40 mL). The solid was dried under high vacuum to afford the product(38a) (6.44 g, 76%) as a solid. ¹H NMR (300 MHz, D₂O): δ 4.30-4.27 (m,2H), 3.75-3.72 (m, 2H), 3.42 (s, 3H), 2.41-2.36 (m, 2H), 1.83-1.78 (m,2H), 1.12 (s, 6H). The spectrum revealed that the product wascontaminated with a small amount of an unidentified substance.

Step 2: Synthesis of 2-methoxyethyl 5-hydroxy-4,4-dimethylpentanoate(38b)

To a suspension of sodium5-(2-methoxyethoxy)-2,2-dimethyl-5-oxopentanoate (38a) (6.44 g, 26.8mmol) in a mixture of THF (58 mL) and DMF (19 mL) was added isopropylchloroformate, 1.0M in toluene (40.2 mL, 40.2 mmol) at 0° C. and stirredfor 10 min. After 4 h of stirring at room temperature, the mixture wasstored at −78° C. overnight. The suspension was cooled to 0° C. andsodium borohydride (1.81 g, 53.6 mmol) was added. The mixture wasstirred for 20 min and then MeOH (9.6 mL) was added to the solution(reaction monitored by TLC using 3:7 EtOAc/hexanes as eluent). After 30min of stirring, EtOAc (50 mL) with a few drops of Et₃N followed by asaturated aqueous solution of NH₄Cl (50 mL) were added. The layers wereseparated and the aqueous layer was extracted with EtOAc (2×80 mL). Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to give the product (38b) (2.54 g,46% crude).

Step 3: Synthesis of 2-methoxyethyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (38c)

A solution of sulfuryl chloride (0.36 mL, 4.9 mmol) in Et₂O (8 mL) wascooled to −78° C. under a nitrogen atmosphere. A solution of2-methoxyethyl 5-hydroxy-4,4-dimethylpentanoate (38b) (0.50 g, 2.4 mmol)and pyridine (0.40 mL, 4.9 mmol) in Et₂O (8 mL) was added dropwise tothe sulfuryl chloride solution over the course of 10 min. The syringewas rinsed with Et₂O (3×1 mL) and the rinse was also added to themixture. The mixture was stirred for 4.5 h (reaction monitored by TLCusing 2:8 EtOAc/hexanes as eluent). The solids were filtered-off and thefiltrate concentrated in vacuo to give the product (38c) (0.60 g, 2.0mmol) as a colorless oil. To this was added 3 mL of THF and the solutionwas stored at −78° C. This was used in the next step without furtherpurification.

Step 4: Synthesis of 2-methoxyethyl5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentanoate(38)

(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (370 mg, 2.0 mmol) was dissolved in THF (19 mL) and HMPA (0.8 mL),and the resulting solution was cooled to −78° C. under an atmosphere ofnitrogen. A 1.0 M solution of NaHMDS in THF (2.2 mL, 2.2 mmol) was addeddropwise to the cooled solution and stirred for 10 min. 2-Methoxyethyl5-((chlorosulfonyl)oxy)-4,4-dimethylpentanoate (38c) (0.60 g, 2.0 mmol)dissolved in THF (3 mL, its temperature maintained at −78° C.) wasquickly added to the reaction mixture. The flask containing thesulfating reagent was rinsed with THF (3×1 mL), while the flasktemperature was maintained at −78° C., and the rinse was quickly addedto the reaction mixture. After stirring for 10 min, the mixture waswarmed to room temperature and stirred overnight. The reaction wasquenched with a saturated solution of aqueous sodium bicarbonate (40 mL)and extracted with EtOAc (40 mL). The organic layer was concentrated,and the oily residue partitioned between H₂O (40 mL) and EtOAc (40 mL).The organic layer was washed with brine, dried (MgSO₄), and concentratedunder vacuum. The residue was purified by column chromatography onsilica gel using EtOAc/hexanes (1:9 to 8:2) as eluent to give theproduct (38) (164 mg, 18%) as a solid. LC-MS: 452.0 [M+H]⁺. ¹H NMR (300MHz, CDCl₃): δ 6.53 (s, 1H), 5.62 (s, 1H), 4.51 (d, J=9.3 Hz, 1H),4.24-4.18 (m, 4H), 4.05-4.03 (m, 1H), 3.61-3.58 (m, 2H), 3.39-3.32 (m,4H), 3.01 (d, J=11.7 Hz, 1H), 2.47-2.33 (m, 3H), 2.18-2.13 (m, 1H),2.00-1.82 (m, 2H), 1.73-1.68 (m, 2H), 0.99 (s, 6H). ¹³C NMR (75 MHz,CDCl₃): δ 173.6, 171.0, 167.1, 83.4, 70.6, 63.7, 62.0, 60.2, 59.1, 47.2,34.2, 33.2, 29.1, 23.6, 23.3, 20.8, 17.6.

Example 39 Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentylpropionate (39)

Step 1: Synthesis of 5,5-dimethyltetrahydro-2H-pyran-2-one (39a)

To a solution of ethyl 5-hydroxy-4,4-dimethylpentanoate (35a) (26.5 g,152.1 mmol) in dichloromethane (683 mL) was added trifluoroacetic acid(1.75 mL, 22.8 mmol). The mixture was stirred at room temperature for 3d. The reaction was quenched with a saturated aqueous sodium bicarbonatesolution (150 mL), stirred rapidly for 30 min, and the layers wereseparated. The organic layer was washed with brine (150 mL), dried(Na₂SO₄), and concentrated under vacuum. The residue was purified bycolumn chromatography on silica gel flash using EtOAc/hexanes (0:1 to45:55) as eluent to give the product (39a) (8.79 g, 45%) as a colorlessoil. The product was used in the next step without further purificationand was contaminated with small amounts of unidentified byproducts. ¹HNMR (300 MHz, CDCl₃): δ 3.97 (s, 2H), 2.56 (t, J=7.4 Hz, 2H), 1.69 (t,J=7.4 Hz, 2H), 1.05 (s, 6H).

Step 2: Synthesis of 3,3,5,5-tetramethyltetrahydro-2H-pyran-2-one (39b)

5,5-Dimethyltetrahydro-2H-pyran-2-one (39a) (8.79 g, 68.6 mmol) wasdissolved in anhydrous DMF (150 mL) and the resulting solution wascooled to 0° C. under an inert atmosphere of argon. Sodium hydride, 60%in mineral oil (8.23 g, 205.7 mmol) was added in one portion and themixture stirred for 20 min. This was followed by the drop-wise additionof MeI (17.1 mL, 274.3 mmol). The resulting solution was stirred at 0°C. for 20 min and then at room temperature for 3 d. The mixture wasdiluted with EtOAc (350 mL) and then quenched at 0° C. via the carefuldropwise addition of a saturated aqueous solution of NH₄Cl (100 mL). Theaqueous and organic layers were separated, and the aqueous layer wasextracted with EtOAc (350 mL). The combined organic layers were washedwith H₂O (6×300 mL), brine (300 mL), dried (Na₂SO₄), and concentratedunder vacuum. The residue was purified by column chromatography onsilica using EtOAc/hexanes (1:9) as eluent to give the product (39b)(3.42 g, 32%). The product was used in the next step without furtherpurification and was contaminated with small amounts of variousunidentified byproducts. ¹H NMR (300 MHz, CDCl₃): δ 4.01 (s, 2H), 1.62(s, 2H), 1.30 (s, 6H), 1.02 (s, 6H).

Step 3: Synthesis of 2,2,4,4-tetramethylpentane-1,5-diol (39c)

A necked round bottom flask containing a stirring slurry of 95% LiAlH₄(0.87 g, 21.6 mmol) in Et₂O (126 mL) was cooled to 0° C. under anatmosphere of argon. To this slurry was added a solution of3,3,5,5-tetramethyltetrahydro-2H-pyran-2-one (39b) (2.94 g, 18.8 mmol)in Et₂O (50 mL) under an inert atmosphere of argon. This was warmed toroom temperature and stirred overnight. The mixture was cautiouslyquenched with H₂O (80 mL) then 3 M NaOH (120 mL) and stirred for 30 min.The mixture was filtered through a pad of Celite®, and the pad wasrinsed thoroughly with Et₂O. The aqueous and organic layers wereseparated, and the aqueous layer was extracted with Et₂O (3×100 mL). Thecombined organic layers were concentrated under vacuum and the residuewas purified by column chromatography on silica gel using EtOAc/hexanes(2:8 to 6:4) as eluent to give the product (39c) (2.59 g, 86%) as asolid. ¹H NMR (300 MHz, CDCl₃): δ 3.41 (s, 4H), 2.55 (s, 2H), 1.34 (s,2H), 0.95 (s, 12H)

Step 4: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl propionate(39d)

To a stirring solution of 2,2,4,4-tetramethylpentane-1,5-diol (39c)(0.48 g, 3.0 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (20 mL) wasadded propionyl chloride (0.26 mL, 3.0 mmol) dropwise over the course of30 min at ca. 0° C. (ice bath). The reaction mixture was stirredovernight at room temperature. The mixture was diluted with H₂O (20 mL),and the layers were separated. The aqueous layer was extracted with DCM(2×20 mL), and the combined organic layers were washed with brine (20mL), dried (Na₂SO₄), and concentrated under vacuum. The residue waspurified by column chromatography on silica gel EtOAc/hexanes (5:95 to6:4) as eluent to give the product (39d) (411 mg, 63%). ¹H NMR (300 MHz,CDCl₃): δ 3.85 (s, 2H), 3.32 (s, 2H), 2.37 (q, J=7.7 Hz, 2H), 1.50 (s,1H), 1.36 (s, 2H), 1.16 (t, J=7.5 Hz, 3H), 1.03 (s, 6H), 0.99 (s 6H).

Step 5: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentylpropionate (39e)

A solution of sulfuryl chloride (0.136 mL, 1.9 mmol) in Et₂O (6.4 mL)was cooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-2,2,4,4-tetramethylpentyl propionate (39d) (404 mg, 1.9 mmol)and pyridine (0.15 mL, 1.9 mmol) in Et₂O (6.4 mL) was added dropwise tothe sulfuryl chloride solution over the course of 10 min. The mixturewas warmed to room temperature and stirred for 70 min. The solids werefiltered to give a solution of the product (39e) in Et₂O as thefiltrate. The yield was assumed quantitative, and the mixture was usedin the next step without further purification.

Step 6: Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentylpropionate (39)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (346 mg, 1.9 mmol) was dissolved in THF (21.8 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (1.0 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A solutionof NaHMDS, 1.0 M in THF (1.9 mL, 1.9 mmol) was added dropwise to thecooled solution and stirred for 90 min. A solution of5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl propionate (39e) (0.59g, 1.9 mmol) in Et₂O (ca. 20 mL) was added to the reaction mixture(cannula). After stirring for 10 min the mixture was warmed to roomtemperature and stirred for 4 h. The reaction was then quenched with asaturated aqueous solution of sodium bicarbonate (40 mL) and extractedwith EtOAc (40 mL). The organic layer was washed with H₂O (3×40 mL),brine (40 mL), dried (Na₂SO₄), and concentrated under vacuum. Theresidue was purified by silica gel flash column chromatography usingEtOAc/hexanes (1:9 to 8:2) as eluent to give the product (39) (254 mg,29%) as a solid. LC-MS: m/z=464.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ6.53 (s, 1H), 5.64 (s, 1H), 4.53 (d, J=9 Hz, 1H), 4.23 (d, J=9 Hz, 1H),4.18 (m, 1H) 4.06-4.04 (m, 1H), 3.80 (s, 2H), 3.36-3.32 (m, 1H), 3.01(d, J=12.3 Hz, 1H), 2.47-2.33 (m, 3H), 2.19-2.13 (m, 1H), 2.01-1.79 (m,2H), 1.43 (s, 2H), 1.16 (t, J=7.7 Hz, 3H), 1.09 (s, 6H), 1.03 (s, 6H).¹³C NMR (75 MHz, CDCl₃): δ 174.6, 171.1, 167.1, 84.9, 73.3, 61.9, 60.2,47.2, 46.2, 36.0, 35.3, 27.8, 26.6, 26.3, 25.9, 25.3, 20.8, 17.5, 9.3.

Example 40 Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentylbenzoate (40)

Step 1: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl benzoate (40a)

To a stirred solution of 2,2,4,4-tetramethylpentane-1,5-diol (39c) (0.48g, 3.0 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (20 mL) was addedbenzoyl chloride (0.37 mL, 3.0 mmol) dropwise over the course of 30 minat ca. 0° C. (ice bath) under an atmosphere of argon. The reactionmixture was stirred overnight at room temperature. The mixture wasdiluted with H₂O (20 mL), and the layers were separated. The aqueouslayer was extracted with DCM (2×20 mL), and the combined organic layerswere washed with brine (20 mL), dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (5:95 to 1:1) as eluent to give the product (40a)(548 mg, 69%) as an oil. ¹H NMR (300 MHz, CDCl₃): δ 8.06 (d, J=8.4 Hz,2H), 7.59-7.55 (m, 1H), 7.48-7.43 (m, 2H), 4.09 (s, 2H), 3.35 (s, 2H),1.48 (s, 2H), 1.13 (s, 6H), 1.02 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentylbenzoate (40b)

A solution of sulfuryl chloride (0.15 mL, 2.0 mmol) in Et₂O (8.5 mL) wascooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-2,2,4,4-tetramethylpentyl benzoate (40a) (541 mg, 2.0 mmol)and pyridine (0.17 mL, 2.0 mmol) in Et₂O (8.5 mL) was added dropwise tothe sulfuryl chloride solution over the course of 10 min. The mixturewas stirred at 0° C. for 20 min, then at room temperature for 90 min.The mixture was filtered and the filtrate used to provide a solution ofthe product (40b) in Et₂O (ca. 20 mL). The yield was assumedquantitative and the product was used in the next step without furtherpurification.

Step 3: Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentylbenzoate (40)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (370 mg, 2.0 mmol) was dissolved in THF (23 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (1.5 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A solutionof NaHMDS, 1.0M in THF (2.0 mL, 2.0 mmol) was added dropwise to thecooled solution and stirred for 90 min. A solution of5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl benzoate (40b) (0.73g, 2.0 mmol, 1.0 equiv.) dissolved in Et₂O (ca. 20 mL) was added to thereaction mixture (cannula). After stirring for 10 min the mixture waswarmed to room temperature and stirred for 4 h. The mixture was quenchedwith a saturated aqueous solution of sodium bicarbonate (40 mL) andextracted with EtOAc (40 mL). The organic layer was washed with H₂O(3×40 mL), brine (40 mL), dried (Na₂SO₄), and concentrated under vacuum.The residue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:9 to 8:2) as eluent to give the product (40) (282 mg,27%) as a solid. LC-MS: m/z=512.15 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ8.06 (d, J=7.8 Hz, 2H), 7.59-7.55 (m, 1H), 7.49-7.43 (m, 2H), 6.49 (s,1H), 5.70 (s, 1H), 4.57 (d, J=9 Hz, 1H), 4.26 (d, J=8.7 Hz, 1H), 4.17(s, 1H), 4.10-4.01 (m, 3H), 3.29-3.25 (m, 1H), 2.98 (d, J=11.7 Hz, 1H),2.45-2.35 (m, 1H), 2.17-2.11 (m, 1H), 1.99-1.77 (m, 2H), 1.56 (s, 2H),1.14-1.13 (m, 12H). ¹³C NMR (75 MHz, CDCl₃): δ 171.0, 167.0, 166.6,133.1, 130.4, 129.7, 128.6, 85.0, 73.9, 61.9, 60.2, 47.2, 46.2, 36.1,35.7, 26.7, 26.4, 25.9, 25.4, 20.8, 17.5.

Example 41 Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl2,6-dimethylbenzoate (41)

Step 1: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl2,6-dimethylbenzoate (41a)

To a stirred solution of 2,2,4,4-tetramethylpentane-1,5-diol (39c) (0.48g, 3.0 mmol) and pyridine (0.24 mL, 3.0 mmol) in DCM (20 mL) was added2,6-dimethylbenzoyl chloride (0.45 mL, 3.0 mmol) dropwise over thecourse of 30 min at 0° C. (ice bath) under an atmosphere of argon. Thereaction mixture was stirred overnight at room temperature. The mixturewas diluted with H₂O (20 mL), and the layers were separated. The aqueouslayer was extracted with DCM (2×20 mL), and the combined organic layerswere washed with brine (20 mL), dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (5:95 to 1:1) as eluent to give the product (41a)(462 mg, 53%) as an oil. ¹H NMR (300 MHz, CDCl₃): δ 7.22-7.17 (m, 1H),7.04 (d, J=7.5 Hz, 2H), 4.10 (s, 2H), 3.32 (s, 2H), 2.33 (s, 6H), 1.41(s, 2H), 1.10 (s, 6H), 1.00 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl2,6-dimethylbenzoate (41b)

A solution of sulfuryl chloride (0.11 mL, 1.5 mmol) in Et₂O (7 mL) wascooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-2,2,4,4-tetramethylpentyl 2,6-dimethylbenzoate (41a) (453 mg,1.5 mmol) and pyridine (0.13 mL, 1.5 mmol) in Et₂O (7 mL) was addeddropwise to the sulfuryl chloride solution over the course of 10 min.The mixture was stirred in an ice bath for 20 min, then at roomtemperature for 90 min. The mixture was filtered and the filtrate storedto give a solution of the product (41b) in Et₂O (ca. 20 mL). The yieldassumed quantitative. This mixture was used in the next step withoutfurther purification (a small quantity was concentrated under vacuum andthe NMR taken of the residue). ¹H NMR (300 MHz, CDCl₃): δ 7.21 (t, J=7.7Hz, 1H), 7.05 (d, J=7.2 Hz, 2H), 4.20 (s, 2H), 4.07 (s, 2H), 2.32 (s,6H), 1.50 (s, 2H), 1.14 (s, 6H), 1.12 (s, 6H).

Step 3: Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl2,6-dimethylbenzoate (41)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (286 mg, 1.5 mmol) was dissolved in THF (18 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (2.3 mL) and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A solutionof NaHMDS, 1.0 M in THF (1.5 mL, 1.5 mmol) was added dropwise to thecooled solution and stirred for 90 min. A solution of5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethylbenzoate(41b) (0.61 g, 1.5 mmol) in Et₂O (ca. 20 mL) was added to the reactionmixture (cannula). After stirring for 10 min the mixture was warmed toroom temperature, stirred for 4 h. The mixture was quenched with asaturated aqueous solution of sodium bicarbonate (40 mL) and extractedwith EtOAc (40 mL). The organic layer was washed with H₂O (3×40 mL),brine (40 mL), dried (Na₂SO₄), and concentrated under vacuum. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (1:9 to 8:2) as eluent to give the product (41) (490 mg,58%) as a solid. LC-MS: m/z=540.07 [M+H]+. ¹H NMR (300 MHz, CDCl₃): δ7.20 (t, J=7.7 Hz, 1H), 7.04 (d, J=7.5 Hz, 2H), 6.50 (s, 1H), 5.63 (s,1H), 4.54 (d, J=8.7 Hz, 1H), 4.23 (d, J=8.7 Hz, 1H), 4.17 (s, 1H),4.06-4.03 (m, 3H), 3.34-3.29 (m, 1H), 3.00 (d, J=11.7 Hz, 1H), 2.47-2.40(m, 1H), 2.32 (s, 6H), 2.18-2.14 (m, 1H), 2.00-1.78 (m, 2H), 1.49 (s,2H), 1.11 (s, 12H). ¹³C NMR (75 MHz, CDCl₃): δ 170.9, 170.4, 167.0,135.0, 134.2, 129.4, 127.7, 84.9, 74.5, 62.0, 60.2, 47.2, 46.2, 36.1,35.4, 26.5, 26.4, 26.0, 25.3, 20.8, 20.0, 17.5.

Example 42 Synthesis of(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42)

Step 1: Synthesis of (3-methyl-2-oxotetrahydrofuran-3-yl)methylsulfochloridate (42a)

Pyridine (0.28 mL, 3.5 mmol) was added to a stirred mixture of3-(hydroxymethyl)-3-methyldihydrofuran-2(3H)-one (prepared according toSynlett 2010, 2625-2627) (0.30 g, 2.3 mmol) and Et₂O (8 mL) under anatmosphere of argon. The solution was cooled to −78° C. and sulfurylchloride (0.28 mL, 3.5 mmol) in Et₂O (3 mL) was slowly added at −78° C.The mixture was stirred at −78° C. for 1 h and then warmed to roomtemperature, and stirred for 1 h. The reaction mixture was filtered toremove the pyridine salt, and the filtrate was concentrated under vacuumto give the product (42a) as an oil, that was used directly in the nextstep without further purification (yield assumed quantitative).

Step 2: Synthesis of(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42)

To a stirred mixture of(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.24 g, 1.3 mmol) in THF (20 mL) under an atmosphere of argon wasadded several drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one. Themixture was cooled to −78° C. and stirred for 10 min, then a solution ofNaHMDS, 1.0M in THF (1.4 mL, 1.4 mmol) was added dropwise. The mixturewas stirred at −78° C. for 8 min, then(3-methyl-2-oxotetrahydrofuran-3-yl)methyl sulfochloridate (42a) (0.30g, 1.3 mmol) in THF (30 mL) was added at −78° C. The mixture was stirredat −78° C. for 10 min, then allowed to warm to room temperature andstirred overnight. The mixture was diluted with EtOAc and saturatedsodium bicarbonate solution. The aqueous and organic layers wereseparated, and the organic layer was washed with water, dried (Na₂SO₄),and concentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 1:0) as eluentto give a solid (150 mg). NMR indicated a trace impurity, which wasremoved by trituration with EtOAc to give the product (42) (35 mg) as asolid. LC/MS: m/z=378.0 [M+H]⁺. ¹H NMR (300 MHz, d₆-DMSO): δ 7.53 (s,1H), 7.38 (s, 1H), 4.68-4.64 (m, 1H), 4.54 (d, J=9.3 Hz, 1H), 4.32-4.27(m, 2H), 4.09 (s, 1H), 3.89 (d, J=6.0 Hz, 1H), 3.21-3.13 (m, 2H),2.38-2.28 (m, 1H), 2.13-2.00 (m, 2H), 1.91-1.66 (m, 3H), 1.21 (s, 3H).¹³C NMR (75 MHz, d₆-DMSO): δ 178.3, 171.0, 168.7, 77.9, 65.6, 61.7,61.2, 46.3, 43.2, 31.2, 20.8, 19.1, 18.9.

(1R,2S,5R)-2-Carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42) was separatedinto its (S) and (R) isomers,(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl(((S)-3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42(S) and(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl(((R)-3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42(R):

Example 43 Synthesis of3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropylpivalate (43)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl pivalate (43a)

To a stirred solution of 2,2-dimethylpropane-1,3-diol (5.07 g, 48.7mmol) in DCM (50 mL) at 0° C. under an atmosphere of argon was addedtrimethylacetyl chloride (2.0 mL, 16.2 mmol), pyridine (2.63 mL, 32.5mmol) and N,N-4-dimethylaminopyridine (0.4 g, 3.2 mmol). The mixture wasallowed to warm to room temperature and stirred at room temperatureovernight. The mixture was cooled to 0° C. and the reaction was quenchedwith the addition of 1N HCl (50 mL), then extracted with DCM (twice).The combined organic layers were washed with sat. sodium bicarbonate andbrine, then dried (Na₂SO₄), and concentrated under vacuum. The residuewas purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 1:5) as eluent to give the product (43a) as an oil. ¹H NMR (300MHz, CDCl₃): δ 3.92 (s, 2H), 3.27 (s, 2H), 1.22 (s, 9H), 0.92 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl pivalate(43b)

Pyridine (0.75 mL, 9.3 mmol) was added to a stirred mixture of3-hydroxy-2,2-dimethylpropyl pivalate (43a) (1.17 g, 6.2 mmol) and Et₂O(20 mL) under an atmosphere of argon. The solution was cooled to −78° C.and sulfuryl chloride (0.75 mL, 9.3 mmol) in Et₂O (8 mL) was slowlyadded at −78° C. The mixture was stirred at −78° C. for 1 h and thenwarmed to room temperature, and stirred for 1 h. The reaction mixturewas filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the product (43b) as an oil, that wasused directly in the next step without further purification (yieldassumed quantitative).

Step 3: Reaction to Produce3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropylpivalate (43)

To a stirred mixture of(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (1.1 g, 5.9 mmol) in THF (20 mL) under an atmosphere of argon wasadded several drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one. Themixture was cooled to −78° C. and stirred for 10 min, then a solution ofNaHMDS, 1.0M in THF (6.5 mL, 6.5 mmol) was added dropwise. The mixturewas stirred at −78° C. for 8 min, then3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl pivalate (43b) (1.7 g, 5.9mmol) in THF (30 mL) was added at −78° C. The mixture was stirred at−78° C. for 10 min, then allowed to warm to room temperature and stirredovernight. The mixture was diluted with EtOAc and saturated sodiumbicarbonate solution. The aqueous and organic layers were separated, andthe organic layer was washed with water, dried (Na₂SO₄), andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 1:0) as eluentto give the product (43) (654 mg) as a solid. LC/MS: m/z=436.0 [M+H]⁺.¹H NMR (300 MHz, CDCl₃): δ 6.48 (s, 1H), 5.58 (s, 1H), 4.60 (d, J=8.7Hz, 1H), 4.36 (d, J=9.0 Hz, 1H), 4.17 (s, 1H), 4.04 (d, J=6.3 Hz, 1H),3.95-3.84 (q, 2H), 3.35-3.31 (m, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.50-2.41(m, 1H), 2.20-2.05 (m, 1H), 1.99-1.78 (m, 2H), 1.22 (s, 9H), 1.04 (s,6H). ¹³C NMR (75 MHz, CDCl₃): δ 178.2, 171.1, 167.1, 80.6, 68.4, 62.0,60.2, 47.2, 39.1, 35.6, 27.3, 21.3, 21.3, 20.8, 17.6.

Example 44 Synthesis of3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl3-chloro-2,6-dimethoxybenzoate (44)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl 2,6-dimethoxybenzoate(44a)

To a stirred solution of 2,2-dimethylpropane-1,3-diol (3.89 g, 37.4mmol) in DCM (40 mL) at 0° C. under an atmosphere of argon was added2,6-dimethoxybenzoyl chloride (80% purity; 3.13 g, 12.5 mmol), pyridine(2.02 mL, 24.9 mmol), and N,N-4-dimethylaminopyridine (0.3 g, 2.5 mmol).The mixture was allowed to warm to room temperature and stirred at roomtemperature overnight. The mixture was cooled to 0° C. and the reactionwas quenched by the addition of 1N HCl (50 mL), then extracted with DCM(twice). The combined organic layers were washed with sat. sodiumbicarbonate and brine, then dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 1:5) as eluent to give the product (44a) asan oil. ¹H NMR (300 MHz, CDCl₃): δ 7.19 (t, J=5.0 Hz, 1H), 6.48 (d,J=8.1 Hz, 2H), 4.09 (s, 2H), 3.71 (s, 6H), 3.33 (s, 2H), 0.89 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl3-chloro-2,6-dimethoxybenzoate (44b)

Pyridine (0.16 mL, 2.0 mmol) was added to a stirred mixture of3-hydroxy-2,2-dimethylpropyl 2,6-dimethoxybenzoate (44a) (0.35 g, 1.3mmol) and Et₂O (10 mL) under an atmosphere of argon. The solution wascooled to −78° C. and sulfuryl chloride (0.16 mL, 2.0 mmol) in Et₂O (8mL) was slowly added at −78° C. The mixture was stirred at −78° C. for 1h and then warmed to room temperature, and stirred for 1 h. The reactionmixture was filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the product (44b) as an oil, that wasused directly in the next step without further purification (yieldassumed quantitative). ¹H NMR (300 MHz, CDCl₃): δ 7.36 (d, J=8.7 Hz,1H), 6.66 (d, J=8.7 Hz, 1H), 4.35 (s, 2H), 4.21 (s, 2H), 3.89 (s, 3H),3.81 (s, 3H), 1.13 (s, 6H).

Step 3: Synthesis of3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl3-chloro-2,6-dimethoxybenzoate (44)

To a stirred mixture of(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (237 mg, 1.3 mmol) in THF (15 mL) under an atmosphere of argon wasadded several drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one. Themixture was cooled to −78° C. and stirred for 10 min, then a solution ofNaHMDS, 1.0M in THF (1.4 mL, 1.4 mmol) was added dropwise. The mixturewas stirred at −78° C. for 8 min, then3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl3-chloro-2,6-dimethoxybenzoate (44b) (0.47 g, 1.2 mmol) in THF (8 mL)was added at −78° C. The mixture was stirred at −78° C. for 10 min, thenallowed to warm to room temperature and stirred overnight. The mixturewas diluted with EtOAc and saturated sodium bicarbonate solution. Theaqueous and organic layers were separated, and the organic layer waswashed with water, dried (Na₂SO₄), and concentrated under vacuum. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 1:0) as eluent to give the product (44) as asolid. LC/MS: m/z=550.0 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.36-7.32(dd, J=1.2 Hz, 1.2 Hz, 1H), 6.65 (d, J=8.1 Hz, 1H), 6.51 (s, 1H), 5.82(s, 1H), 4.55 (d, J=8.7 Hz, 1H), 4.38 (d, J=9.0 Hz, 1H), 4.25-4.07 (m,3H), 4.01 (d, J=6.6 Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.27 (d, J=11.7Hz, 1H), 2.98 (d, J=11.7 Hz, 1H), 2.41-2.37 (m, 1H), 2.14-2.10 (m, 1H),1.94-1.74 (m, 2H), 1.08 (s, 6H). ¹³C NMR (75 MHz, CDCl₃): δ 171.1,167.1, 165.2, 156.1, 153.7, 131.7, 119.8, 119.5, 107.9, 80.4, 69.3,62.2, 62.0, 60.2, 56.3, 47.1, 35.7, 21.3, 21.2, 20.8, 17.5.

Example 45 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl2,6-dimethylbenzoate (45)

Step 1: Synthesis of 2,2,3,3-tetramethylbutane-1,4-diol (45a)

A solution of 3,3,4,4-tetramethyldihydrofuran-2(3H)-one (preparedaccording to U.S. Pat. No. 3,658,849) (1.0 g, 7.0 mmol) in Et₂O (28 mL)was added to a stirring slurry of LiAlH₄ (95%; 0.32 g, 8.1 mmol) in Et₂O(28 mL) at 0° C. under an atmosphere of argon. The mixture was warmed toroom temperature and stirred overnight. Sodium sulfate decahydrate wasslowly added until effervescence in the flask ceased. The solid wasfiltered through a pad of Celite®, and the pad was washed with EtOAc.The filtrate was concentrated under vacuum, and the residue was purifiedby column chromatography on silica gel using EtOAc/hexanes (0:1 to 7:3)as eluent to give the product (45a) (0.7 g) as a solid. ¹H NMR (300 MHz,CDCl₃): δ 3.41 (s, 4H), 0.88 (s, 12H).

Step 2: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl2,6-dimethylbenzoate (45b)

To a stirred solution of 2,2,3,3-tetramethylbutane-1,4-diol (45a) (0.71g, 4.9 mmol) in DCM (15 mL) at 0° C. under an atmosphere of argon wasadded 2,6-dimethylbenzoyl chloride (0.2 mL, 1.6 mmol), pyridine (0.26mL, 3.2 mmol) and N,N-4-dimethylaminopyridine (0.04 g, 0.3 mmol). Themixture was allowed to warm to room temperature and stirred at roomtemperature overnight. The mixture was cooled to 0° C. and the reactionwas quenched by the addition of 1N HCl (15 mL), then extracted with DCM(twice). The combined organic layers were washed with sat. sodiumbicarbonate and brine, then dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 3:2) as eluent to give the product (45b) asan oil (266 mg). ¹H NMR (300 MHz, CDCl₃): δ 7.18 (t, J=8.4 Hz, 1H), 7.02(d, J=6.9 Hz, 2H), 4.25 (s, 2H), 3.51 (s, 2H), 2.31 (s, 6H), 0.98 (s,6H), 0.93 (s, 6H).

Step 3: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl2,6-dimethylbenzoate (45c)

Pyridine (0.11 mL, 1.3 mmol) was added to a stirred mixture of4-hydroxy-2,2,3,3-tetramethylbutyl 2,6-dimethylbenzoate (45b) (0.26 g,0.9 mmol) and Et₂O (10 mL) under an atmosphere of argon. The solutionwas cooled to −78° C. and sulfuryl chloride (0.11 mL, 1.3 mmol) in Et₂O(3 mL) was slowly added at −78° C. The mixture was stirred at −78° C.for 1 h and then warmed to room temperature, and stirred for 1 h. Thereaction mixture was filtered to remove the pyridine salt, and thefiltrate was concentrated under vacuum to give the product (45c) as anoil, that was used directly in the next step without furtherpurification (yield assumed quantitative).

Step 3: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl2,6-dimethylbenzoate (45)

To a stirred mixture of(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (255 mg, 1.4 mmol) in THF (10 mL) under an atmosphere of argon wasadded several drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one. Themixture was cooled to −78° C. and stirred for 10 min, then a solution ofNaHMDS, 1.0M in THF (1.5 mL, 1.5 mmol) was added dropwise. The mixturewas stirred at −78° C. for 8 min, then4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl 2,6-dimethylbenzoate(45c) (0.52 g, 1.4 mmol) in THF (5 mL) was added at −78° C. The mixturewas stirred at −78° C. for 10 min, and then allowed to warm to roomtemperature and stirred for 1 h. The mixture was diluted with EtOAc andsaturated sodium bicarbonate solution. The aqueous and organic layerswere separated, and the organic layer was washed with water, dried(Na₂SO₄), and concentrated under vacuum. The residue was purified bycolumn chromatography on silica gel using EtOAc/hexanes (0:1 to 1:0) aseluent to give the product (45) as a solid. LC/MS: m/z=526.16 [M+H]⁺. ¹HNMR (300 MHz, CDCl₃): δ 7.19 (t, J=7.7 Hz, 1H), 7.03 (d, J=6.9 Hz, 2H),6.47 (s, 1H), 5.58 (s, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.40 (d, J=9.6 Hz,1H), 4.20-4.16 (m, 3H), 4.04 (d, J=6.3 Hz, 1H), 3.33 (d, J=12.3 Hz, 1H),2.99 (d, J=12.3 Hz, 1H), 2.45-2.40 (m, 1H), 2.32 (s, 6H), 2.17-2.13 (m,1H), 2.04-1.83 (m. 2H), 1.05-1.03 (m, 12H). ¹³C NMR (75 MHz, CDCl₃): δ170.9, 170.4, 167.1, 134.9, 134.2, 129.4, 127.6, 82.1, 70.8, 62.0, 60.2,47.3, 39.1, 38.5, 21.0, 20.9, 20.8, 20.5, 20.3, 20.0, 17.5.

Example 46 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutylbenzoate (46)

Step 1: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl benzoate (46a)

To a stirred solution of 2,2,3,3-tetramethylbutane-1,4-diol (45a) (0.74g, 5.0 mmol) in DCM (15 mL) at 0° C. under an atmosphere of argon wasadded benzoyl chloride (0.25 mL, 2.0 mmol), pyridine (0.33 mL, 4.0 mmol)and N,N-4-dimethylaminopyridine (0.05 g, 0.4 mmol). The mixture wasallowed to warm to room temperature and stirred at room temperatureovernight. The mixture was cooled to 0° C. and the reaction was quenchedby the addition of 1N HCl (15 mL), then extracted with DCM (twice). Thecombined organic layers were washed with sat. sodium bicarbonate andbrine, then dried (Na₂SO₄), and concentrated under vacuum. The residuewas purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 3:2) as eluent to give the product (46a) as an oil. ¹H NMR (300MHz, CDCl₃): δ 8.05 (d, J=7.2 Hz, 2H), 7.58 (t, J=7.4 Hz, 1H), 7.46 (t,J=7.4 Hz, 2H), 4.27 (s, 2H), 3.59 (s, 2H), 1.05 (s, 6H), 0.99 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutylbenzoate (46b)

Pyridine (0.29 mL, 3.6 mmol) was added to a stirred mixture of4-hydroxy-2,2,3,3-tetramethylbutyl benzoate (46a) (0.70 g, 2.8 mmol) andEt₂O (10 mL) under an atmosphere of argon. The solution was cooled to−78° C. and sulfuryl chloride (0.29 mL, 3.6 mmol) in Et₂O (3 mL) wasslowly added at −78° C. The mixture was stirred at −78° C. for 1 h andthen warmed to room temperature, and stirred for 1 h. The reactionmixture was filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the product (46b) as an oil, that wasused directly in the next step without further purification (yieldassumed quantitative).

Step 3: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutylbenzoate (46)

To a stirred mixture of(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.52 g, 2.8 mmol) in THF (10 mL) under an atmosphere of argon wasadded several drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one. Themixture was cooled to −78° C. and stirred for 10 min, then a solution ofNaHMDS, 1.0M in THF (3.1 mL, 3.1 mmol), was added dropwise. The mixturewas stirred at −78° C. for 8 min, and then4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl benzoate (46b) (0.98 g,2.8 mmol) in THF (5 mL) was added at −78° C. The mixture was stirred at−78° C. for 10 min, and then allowed to warm to room temperature andstirred for 1 h. The mixture was diluted with EtOAc and saturated sodiumbicarbonate solution. The aqueous and organic layers were separated, andthe organic layer was washed with water, dried (Na₂SO₄), andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 1:0) as eluentto give the product (46) as a solid. LC/MS: m/z=498.10 [M+H]⁺. ¹H NMR(300 MHz, CDCl₃): δ 8.05 (d, J=7.2 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.45(t, J=7.4 Hz, 2H), 6.47 (s, 1H), 5.61 (s, 1H), 4.87 (d, J=9.0 Hz, 1H),4.52 (d, J=9.3 Hz, 1H), 4.22-4.17 (m, 3H), 4.01 (d, J=6.3 Hz, 1H),3.35-3.31 (m, 1H), 2.99 (d, J=14.7 Hz, 1H), 2.43-2.39 (m, 1H), 2.17-2.12(m, 1H), 1.92-1.81 (m, 2H), 1.10-1.06 (m, 12H). ¹³C NMR (75 MHz, CDCl₃):δ 170.9, 167.1, 166.6, 133.1, 130.3, 129.7, 128.6, 82.4, 70.5, 62.0,60.2, 47.3, 39.2, 38.8, 21.1, 21.0, 20.8, 20.5, 20.3, 17.5.

Example 47 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutylpropionate (47)

Step 1: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl propionate (47a)

To a stirred solution of 2,2,3,3-tetramethylbutane-1,4-diol (45a) (0.59g, 4.0 mmol) in DCM (15 mL) at 0° C. under an atmosphere of argon wasadded propionyl chloride (0.25 mL, 3.1 mmol), pyridine (0.33 mL, 4.0mmol) and N,N-4-dimethylaminopyridine (0.05 g, 0.4 mmol). The mixturewas allowed to warm to room temperature and stirred at room temperatureovernight. The mixture was cooled to 0° C. and the reaction was quenchedby the addition of 1N HCl (15 mL), and then extracted with DCM (twice).The combined organic layers were washed with sat. sodium bicarbonate andbrine, then dried (Na₂SO₄), and concentrated under vacuum. The residuewas purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 3:2) as eluent to give di-acylated material, followed by theproduct (47a) (300 mg) as an oil. ¹H NMR (300 MHz, CDCl₃): δ 3.99 (s,2H), 3.49 (s, 2H), 2.38-2.31 (q, 2H), 1.15 (t, J=7.8 Hz, 3H), 0.91 (d,J=4.8 Hz, 12H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutylpropionate (47b)

Pyridine (0.16 mL, 1.9 mmol) was added to a stirred mixture of4-hydroxy-2,2,3,3-tetramethylbutyl propionate (47a) (0.30 g, 1.5 mmol)and Et₂O (10 mL) under an atmosphere of argon. The solution was cooledto −78° C. and sulfuryl chloride (0.16 mL, 1.9 mmol) in Et₂O (3 mL) wasslowly added at −78° C. The mixture was stirred at −78° C. for 1 h andthen warmed to room temperature, and stirred for 1 h. The reactionmixture was filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the product (47b) as an oil, that wasused directly in the next step without further purification (yieldassumed quantitative).

Step 3: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutylpropionate (47)

To a stirred mixture of(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide91) (271 mg, 1.5 mmol) in THF (10 mL) under an atmosphere of argon wasadded several drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one. Themixture was cooled to −78° C. and stirred for 10 min, then a solution ofNaHMDS, 1.0M in THF (1.6 mL, 1.6 mmol) was added dropwise. The mixturewas stirred at −78° C. for 8 min, then4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl propionate (47b) (0.44g, 1.5 mmol) in THF (5 mL) was added at −78° C. The mixture was stirredat −78° C. for 10 min, then allowed to warm to room temperature andstirred for 1 h. The mixture was diluted with EtOAc and saturated sodiumbicarbonate solution. The aqueous and organic layers were separated, andthe organic layer was washed with water, dried (Na₂SO₄), andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 1:0) as eluentto give the product (47) (300 mg) as a solid. LC/MS: m/z=450.09 [M+H]⁺.¹H NMR (300 MHz, CDCl₃): δ 6.49 (s, 1H), 5.62 (s, 1H), 4.77 (d, J=8.7Hz, 1H), 4.45 (d, J=9.3 Hz, 1H), 4.19 (s, 1H), 4.05 (d, J=6.3 Hz, 1H),3.95 (s, 2H), 3.35 (d, J=12.0 Hz, 1H), 3.01 (d, J=12.3 Hz, 1H),2.46-2.34 (m, 3H), 2.19-2.15 (m, 1H), 1.92-1.83 (m, 2H), 1.16 (t, J=7.7Hz, 3H), 1.01 (d, J=9.3 Hz, 6H), 0.96 (s, 6H). ¹³C NMR (75 MHz, CDCl₃):δ 174.5, 171.0, 167.1, 82.5, 70.0, 62.0, 60.2, 47.3, 39.1, 38.4, 27.8,21.0, 20.9, 20.8, 20.4, 20.2, 17.5, 9.3.

Example 48 Synthesis of(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methyl) sulfate (48)

Step 1: Synthesis of3-((benzyloxy)methyl)-3-methyltetrahydro-2H-pyran-2-one (48a)

6-Valerolactone (5.23 g, 52.2 mmol) was dissolved in a mixture of THF(120 mL) and HMPA (9.2 mL) under an atmosphere of argon. The reactionmixture was cooled to −78° C. and stirred for 10 min. A solution oflithium diisopropylamide, 2.0 M in THF (28.7 mL, 57.5 mmol) was addeddropwise over 5 min. The reaction was stirred at −78° C. for 30 min andthen neat MeI (3.3 mL, 52.8 mmol) was added to the reaction over 5 min.The mixture was stirred at −78° C. for 30 min then removed from thecooling bath and allowed to warm to 0° C. and stirred for 30 min (note:the mixture gradually became yellow during this time). The mixture wasre-cooled to −78° C. and stirred for 10 min, and then an additionalamount of lithium diisopropylamide, 2.0 M in THF (28.7 mL, 57.5 mmol)was added over 5 min. The reaction was stirred at −78° C. for 30 min,then neat benzyl chloromethyl ether (70%; 10.5 mL, 52.8 mmol) was addedover 5 min. The mixture was left to warm to room temperature and stirredfor 16 h. The solvent was then removed under vacuum and the residue waspartitioned between saturated ammonium chloride (200 mL) and EtOAc (200mL). The aqueous layer was extracted with EtOAc (2×100 mL) and thecombined organic layers were washed with brine (2×100 mL), dried(Na₂SO₄), filtered, and concentrated under vacuum (19 g). The residuewas dry-loaded onto silica gel and purified by column chromatography onsilica gel (120 g cartridge) using EtOAc/hexanes as eluent to give theproduct contaminated with an impurity (6.9 g). The residue wasre-purified by column chromatography on silica gel using DCM/hexanes(0:1 to 4:1) as eluent to give the product (48a) (1.76 g) as a liquid.¹H NMR (300 MHz, CDCl₃): δ 7.29-7.37 (m, 5H), 4.61 (dd, J=21.0, 12.3 Hz,2H), 4.32-4.38 (m, 2H), 3.26-3.81 (dd, J=15.8, 8.1 Hz, 2H), 2.21-2.30(m, 1H), 1.87-1.94 (m, 2H), 1.59-1.66 (m, 1H), 1.23 (s, 3H).

Step 2: Synthesis of 3-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2-one(48b)

3-((Benzyloxy)methyl)-3-methyltetrahydro-2H-pyran-2-one (48a) (0.52 g,2.2 mmol) was dissolved in 2-propanol (25 mL) and the solution wasdegassed and back-flushed with argon. (Note: do not use MeOH as solvent,as it may ring-open the lactone during hydrogenation). Palladium oncarbon, 10% (0.26 g, 0.2 mmol), was added to the mixture and the systemwas sealed. The reaction was degassed and back-flushed with hydrogen (3times) and stirred under an atmosphere of hydrogen for 2 h. Thesuspension was filtered through a pad of Celite®, and the filter cakewashed with fresh 2-propanol (2×50 mL). The filtrate was concentratedunder vacuum, and the product (48b) was used without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ 4.27-4.45 (m, 2H), 3.67 (d,J=11.4 Hz, 1H), 3.52 (d, J=11.1 Hz, 1H), 1.84-2.03 (m, 2H), 1.58-1.64(m, 1H), 1.29 (s, 3H).

Step 3: Synthesis of (3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methylsulfochloridate (48c)

A solution of 3-(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2-one (48b)(0.32 g, 2.2 mmol) and pyridine (0.21 mL, 2.6 mmol) in Et₂O (10 mL) wascooled to −78° C. under an atmosphere of argon. Neat sulfuryl chloride(0.21 mL, 2.6 mmol) was added dropwise to the above solution via asyringe. The mixture was stirred at −78° C. for 10 min, then the flaskwas warmed to room temperature and stirred for 1 h (monitored by TLCEtOAc/hexanes, 3:7). A precipitate formed to give a thick suspension.The suspension was filtered through a 0.45 μM Teflon® filter, and thefilter cake rinsed with fresh Et₂O (2×5 mL). An aliquot (0.5 mL) wastaken and concentrated, and an NMR was obtained for the mixture. Theremaining solution containing the product (48c) was used directly in thenext step. ¹H NMR (300 MHz, CDCl₃): δ 4.87 (d, J=9.3 Hz, 1H), 4.25-4.50(m, 2H), 4.32 (d, J=8.7 Hz, 1H), 2.00-2.20 (m, 2H), 1.75-2.00 (m, 2H),1.39 (s, 3H).

Step 4: Synthesis of(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methyl) sulfate (48)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.39 g, 2.1 mmol) was dissolved in THF (18 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (0.65 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of argon. NaHMDS, 1.0M in THF (2.3 mL, 2.3 mmol) was added dropwise to the cooled solutionand stirred for 1 h. A solution of(3-methyl-2-oxotetrahydro-2H-pyran-3-yl)methyl sulfochloridate (48c)(0.51 g, 2.1 mmol) in Et₂O (from the previous reaction) was addedquickly to the reaction mixture. The mixture was allowed to warm to roomtemperature and stirred overnight. Brine (100 mL) and EtOAc (100 mL)were added to the reaction mixture and the aqueous and organic layerswere separated. The aqueous layer was extracted with EtOAc (2×100 mL),and the combined organic layers were washed with brine (3×100 mL), dried(Na₂SO₄), and concentrated under vacuum. The residue was dry-loaded ontosilica gel (8 g) and purified by column chromatography on silica gelusing with EtOAc/hexanes (1:4 to 1:0) as eluent to give the desiredproduct (48) (0.21 g) as a solid. LC-MS: m/z=392 [M+H]⁺. ¹H NMR (300MHz, CDCl₃): δ 6.55 (br. d, J=9.3 Hz, 1H), 5.77 (br. s, 1H), 4.83-5.03(m, 1H), 4.56 (m, 0.5H), 4.33-4.45 (m, 2.5H), 4.17 (m, 1H), 4.06 (m,1H), 3.35 (d, J=9.3 Hz, 1H), 3.04 (m, 1H), 2.38-2.44 (m, 1H), 1.68-2.20(m, 7H), 1.36 (d, J=7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 172.8,172.5, 171.2, 171.0, 167.3, 167.1, 80.4, 79.9, 76.7, 70.8, 70.8, 62.0,60.3, 60.2, 47.2, 47.1, 43.1, 43.0, 29.8, 29.6, 22.9, 22.9, 20.9 20.8,20.17. (Note: there are several signals that are split due to chiralityin the lactone product).

Example 49 Synthesis of2-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)phenylacetate (49)

Step 1: Synthesis of ethyl 3-(2-methoxyphenyl)-2,2-dimethylpropanoate(49a)

A stirred solution of lithium diisopropylamide, 2.0 M in THF (26.6 mL,53.2 mmol) was diluted with THF (100 mL) was cooled to −78° C. under anatmosphere of argon, and stirred for 5 min. Neat ethyl isobutyrate (6.68mL, 49.7 mmol) was added dropwise over 15 min, and the mixture allowedto stir at −78° C. for 1 h. A solution of1-(bromomethyl)-2-methoxybenzene (prepared according to J. Am. Chem.Soc. 2013, 135, 11951) (12.0 g, 59.7 mmol) in THF (100 mL) was addeddropwise over 30 min. The mixture was allowed to warm to roomtemperature and stirred for 20 h. The reaction was quenched with brine(100 mL) and extracted with Et₂O (4×100 mL). The combined organic layerswere dried (MgSO₄), filtered, and concentrated under vacuum. The cruderesidue was purified by column chromatography on silica gel (120 gcolumn) using EtOAc/hexanes (0:1 to 5:95) as eluent to give the product(49a) as a liquid (8.06 g, 68%). ¹H NMR (300 MHz, CDCl₃): δ 7.18 (dt,J=1.8, 8.1 Hz, 1H), 7.06 (dd, J=1.5, 8.1 Hz, 1H), 6.82-6.87 (m, 2H),4.12 (q, J=6.9 Hz, 2H), 3.77 (s, 3H), 2.92 (s, 2H), 1.26 (t, J=6.9 Hz,3H), 1.15 (s, 6H).

Step 2: Synthesis of 3,3-dimethylchroman-2-one (49b)

Ethyl 3-(2-methoxyphenyl)-2,2-dimethylpropanoate (49a) (8.1 g, 34.2mmol) was dissolved in DCM (200 mL) and cooled to 0° C. under anatmosphere of argon. A solution of BBr₃ (3.6 mL, 37.7 mmol) in DCM (100mL) was added dropwise to the cold solution. The mixture was warmed toroom temperature and stirred overnight (a solid formed during thereaction). The colored suspension was cooled in an ice water bath andwater (150 mL) was added to the mixture. The organic and aqueous layerswere separated, and the aqueous layer was extracted with DCM (3×75 mL).The combined organic layers were dried (MgSO₄; note: the solution becamedarker), filtered, and concentrated under vacuum to give the product(49b) (4.85 g, 80%) as an oil. This material was used without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ 7.01-7.25 (m, 3H), 2.85 (s,2H), 1.29 (s, 6H).

Step 3: Synthesis of 2-(3-hydroxy-2,2-dimethylpropyl)phenol (49c)

LiAlH₄ (1.94 g, 51.1 mmol) was suspended in Et₂O (52.5 mL) under anatmosphere of argon and the mixture was cooled to 0° C. in an ice waterbath. A solution of 3,3-dimethylchroman-2-one (49b) (4.85 g, 27.5 mmol)in Et₂O (50 mL) and added dropwise to the suspension over 30 min. Themixture was warmed to room temperature and stirred for 20 h. The mixturewas cooled in an ice water bath and water (2 mL), 15% aqueous sodiumhydroxide (2 mL), and water (6 mL), were sequentially added by slowaddition. The mixture was warmed to room temperature and stirred for 15min. Anhydrous MgSO₄ was added to the suspension and the mixture stirredfor 15 min. The mixture was filtered, and the filter cake washed withEt₂O (3×50 mL). The filtrate was concentrated under vacuum to give theproduct (49c) (4.34 g, 88%) as a solid. This material was used withoutfurther purification. ¹H NMR (300 MHz, CDCl₃): δ 7.15 (dt, J=8.1, 1.5Hz, 1H), 7.04 (dd, J=7.5, 1.8 Hz, 1H), 6.82-7.01 (m, 2H), 3.22 (s, 2H),2.61 (s, 2H), 0.98 (s, 6H).

Step 4: Synthesis of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenol (49d)

A solution of 2-(3-hydroxy-2,2-dimethylpropyl)phenol (49c) (4.0 g, 22.2mmol) and imidazole (3.8 g, 56.0 mmol) was dissolved in DMF (50 mL) andtert-butyldimethylsilyl chloride (4.0 g, 26.6 mmol) was added to thesolution and stirred for 2 h. The solvent was removed under high vacuumand the residue was purified by column chromatography on silica gel (40g cartridge) with hexanes (5:95 to 2:3) as eluent to give the product(49d) as an oil (7.34 g, >100%). The compound was approximately 90% pureand was used directly in the next step without further purification. ¹HNMR (300 MHz, CDCl₃): δ 7.11 (dt, J=7.5, 1.8 Hz, 1H), 7.10 (dd, J=7.5,1.8 Hz, 1H), 6.90 (dd, J=8.1, 1.5 Hz, 1H), 6.79 (dt, J=6.9, 0.9 Hz, 1H),3.17 (s, 2H), 2.57 (s, 2H), 0.97 (s, 9H), 0.92 (s, 6H), 0.13 (s, 6H).

Step 5: Synthesis of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl acetate(49e)

A solution of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenol (49d) (ca.90% purity; 2.5 g, 7.6 mmol) and Et₃N (2.3 g, 22.9 mmol) in THF (90 mL)was cooled to 0° C. in an ice bath under an atmosphere of argon. Acetylchloride (0.65 mL, 9.2 mmol) was added dropwise to the mixture, andafter complete addition the ice bath was removed. The reaction wasallowed to warm to room temperature and stirred for 2 h. The suspensionwas filtered and the solid washed with fresh THF (2×20 mL). The filtratewas concentrated under vacuum and the residue dry-loaded onto silicagel, then purified by column chromatography on silica gel (40 gcartridge) using 0-8% EtOAc/hexanes (0:1 to 8:92) as eluent to give theproduct (49e) (2.16 g, 84%) as an oil. ¹H NMR (300 MHz, CDCl₃): δ7.11-7.27 (m, 3H), 7.04 (d, J=7.5 Hz, 1H), 3.25 (s, 2H), 2.51 (s, 2H),2.30 (s, 3H), 0.93 (s, 9H), 0.81 (s, 6H), 0.06 (s, 6H).

Step 6: Synthesis of 2-(3-hydroxy-2,2-dimethylpropyl)phenyl acetate and3-(2-hydroxyphenyl)-2,2-dimethylpropyl acetate (49f)

Pyridine hydrofluoride (70%, 1.3 mL, 10.4 mmol) was added to a stirredsolution of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl acetate(49e) (0.70 g, 2.1 mmol) and pyridine (2.5 mL, 31.2 mmol) in THF (25 mL)at room temperature under an atmosphere of argon, and the mixture wasstirred for 24 h. The solvent was removed under vacuum (bath temperatureset to 25° C.), and the residue was dissolved in EtOAc (100 mL), washedwith brine (3×75 mL), dried (Na₂SO₄), filtered, and concentrated undervacuum to give a mixture of the desired alcohol and3-(2-hydroxyphenyl)-2,2-dimethylpropyl acetate in a 65:35. NMR analysisshowed the presence of both esters of the product (49f). This materialwas used directly in the next step without further purification. ¹H NMR(300 MHz, CDCl₃) of desired product: δ 6.8-7.26 (m, 4H), 3.79 (s, 2H),3.27 (s, 2H), 2.62 (s, 2H), 2.53 (s, 2H), 2.33 (s, 3H), 2.13 (s, 3H),0.974 (s, 6H), 0.90 (s, 6H).

Step 7: Synthesis of2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl acetate (49g)

A solution of sulfuryl chloride (172 μL, 2.1 mmol) in Et₂O (6.8 mL) wascooled to −78° C. under an atmosphere of argon. A solution of2-(3-hydroxy-2,2-dimethylpropyl)phenyl acetate (49f) (0.43 g, 1.9 mmol)and pyridine (172 μL, 2.1 mmol) in Et₂O (2.0 mL) was added dropwise tothe sulfuryl chloride solution via cannula. The mixture was stirred at−78° C. for 10 min, then the flask was warmed to room temperature andstirred for 1.5 h (monitored by TLC 30% EtOAc/hexanes). The suspensionwas filtered through a 0.45 m PTFE syringe filter, and the syringefilter was rinsed with fresh Et₂O (10 mL) to provide the product (49g).The filtrate was used immediately in the next step without furtherpurification. The yield was assumed to be quantitative.

Step 8: Synthesis of2-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)phenylacetate (49)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.44 g, 2.4 mmol) was dissolved in THF (22 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (0.8 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A solutionof NaHMDS, 1.0 M in THF (2.1 mL, 2.1 mmol) was added dropwise to thecooled solution and stirred for 10 min. A solution of2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl acetate (49g) (0.62g, 1.9 mmol) in Et₂O from the previous reaction was quickly added to thereaction mixture. After 10 min, the reaction mixture was warmed to roomtemperature and stirred overnight. Brine (100 mL) was added to thereaction mixture and the aqueous and organic layers were separated. Theaqueous layer was extracted with EtOAc (2×200 mL) and the combinedorganic layers were washed with brine (3×75 mL), dried (Na₂SO₄),filtered, and concentrated under vacuum. The residue was dissolved inDMF (6 mL) and filtered through a 0.45 m frit, and then purified bypreparative HPLC with 20-90% MeCN/water (no modifier) as eluent to givethe product (49) (0.18 g, 20%) as a solid. LC-MS: m/z=470 [M+H]+. ¹H NMR(300 MHz, CDCl₃): δ 7.23-7.29 (m, 1H), 7.18-7.20 (m, 2H), 7.08 (d, J=7.5Hz, 1H), 6.52 (br. s, 1H), 5.78 (br. s, 1H), 4.55 (d, J=7.5 Hz, 1H),4.19-4.22 (m, 2H), 4.05 (br. d, J=7.2 Hz, 1H), 3.30 (br. d, J=11.7 Hz,1H), 2.99 (d, J=11.7 Hz, 1H), 2.51-2.62 (m, 2H), 2.39-2.44 (m, 1H), 2.34(s, 3H), 2.10-2.19 (m, 1H), 1.84-2.00 (m, 2H), 0.98 (d, J=3.0 Hz, 6H).¹³C NMR (75 MHz, CDCl₃): δ 171.1, 169.6, 167.1, 149.6, 132.8, 129.1,128.0, 125.8, 122.7, 83.4, 62.0, 60.3, 47.2, 38.1, 36.3, 23.7, 21.3,20.8, 17.6.

Example (50) Synthesis of2-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)phenylpivalate (50)

Step 1: Synthesis of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl pivalate(50a)

2-(3-((tert-Butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenol (0.9 g,3.1 mmol) and N,N-4-dimethylaminopyridine (0.93 g, 7.6 mmol) weredissolved in THF (50 mL) under an atmosphere of argon. Trimethylacetylchloride (0.45 mL, 3.7 mmol) was added dropwise to the mixture at roomtemperature to immediately form a white solid, and the addition wascontinued until a suspension was formed. The reaction was stirred atroom temperature for 2 h, and then filtered and the filter cake washedwith THF (10 mL). The filtrate was dry-loaded on to silica gel (15 g)and purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 6:94) as eluent to give the product (50a) contaminated with ca.3% of starting material by NMR analysis. This material was used withoutfurther purification. ¹H NMR (300 MHz, CDCl₃): δ 7.27 (dd, J=7.2, 2.1Hz, 1H), 7.21 (dt, J=7.5, 1.8 Hz, 1H), 7.15 (dt, J=7.8, 1.8 Hz, 1H),6.97 (dd, J=8.1, 1.8 Hz, 1H), 3.25 (s, 2H), 2.49 (s, 2H), 1.38 (s, 9H),0.92 (s, 9H), 0.82 (s, 6H), 0.05 (s 6H).

Step 2: Synthesis of 2-(3-hydroxy-2,2-dimethylpropyl)phenyl pivalate(50b)

Pyridine hydrofluoride (70%, 1.3 mL, 10.4 mmol) was added to a stirredsolution of2-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)phenyl pivalate(50a) (0.70 g, 1.8 mmol) and pyridine (2.5 mL, 31.2 mmol) in THF (25 mL)at room temperature under an atmosphere of argon, and the mixture wasstirred for 24 h. The solvent was removed under vacuum (bath temperatureset to 25° C.), and the residue was dissolved in EtOAc (100 mL) andwashed with brine (3×75 mL), dried (Na₂SO₄), filtered, and concentratedunder vacuum to give the desired product (50b) as an oil. This materialwas used directly in the next step without further purification. ¹H NMR(300 MHz, CDCl₃): δ 7.12-7.26 (m, 3H), 6.98 (m, 1H), 3.31 (s, 2H), 2.51(s, 2H), 1.39 (s, 9H), 0.89 (s, 9H).

Step 3: Synthesis of2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl pivalate (50c)

A solution of sulfuryl chloride (173 μL, 2.1 mmol) in Et₂O (7.5 mL) wascooled to −78° C. under an argon atmosphere. A solution of2-(3-hydroxy-2,2-dimethylpropyl)phenyl pivalate (50b) (0.47 g, 1.8 mmol)and pyridine (173 μL, 2.1 mmol) in Et₂O (2.2 mL) was added dropwise tothe sulfuryl chloride solution via cannula. The mixture was stirred at−78° C. for 10 min, and then the flask was warmed to room temperatureand stirred for 1.5 h (monitored by TLC 30% EtOAc/hexanes). Thesuspension was filtered through a 0.45-μm PTFE syringe filter, and thesyringe filter was rinsed with fresh Et₂O to provide the product (50c).The filtrate was used immediately in the next step without furtherpurification. The yield was assumed to be quantitative.

Step 4: Synthesis of2-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)phenylpivalate (50)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.41 g, 2.2 mmol) was dissolved in THF (23 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (0.8 mL), and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A solutionof NaHMDS, 1.0 M in THF (2.2 mL, 2.2 mmol) was added dropwise to thecooled solution and the solution stirred for 10 min. A solution of2-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)phenyl pivalate (50c)(0.65 g, 1.8 mmol) in Et₂O from the previous reaction was added quicklyto the reaction mixture. After 10 min, the reaction mixture was warmedto room temperature and stirred overnight. Brine (100 mL) was added tothe reaction mixture and the aqueous and organic layers were separated.The aqueous layer was extracted with EtOAc (2×200 mL) and the combinedorganic layers were washed with brine (3×75 mL), dried (Na₂SO₄),filtered, and concentrated under vacuum. The residue was dissolved inDMF (6 mL) and filtered through a 0.45-μm frit, and then purified bypreparative HPLC to give the product (50) (0.21 g, 23%) as a solid.LC-MS: m/z=512 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.12-7.28 (m, 3H),6.99 (d, J=7.5 Hz, 1H), 6.50 (br. s, 1H), 5.78 (br. s, 1H), 4.57 (d,J=9.3 Hz, 1H), 4.26 (d, J=8.7 Hz, 1H), 4.17 (br. s, 1H), 4.04 (d, J=6.3Hz, 1H), 3.28 (br. d, J=11.7 Hz, 1H), 3.03 (d, J=11.7 Hz, 1H), 2.52-2.62(m, 2H), 2.39-2.50 (m, 1H), 2.10-2.20 (m, 1H), 1.78-1.98 (m, 2H), 1.38(s, 9H), 0.97 (d, J=4.2 Hz, 6H). ¹³C NMR (75 MHz, CDCl₃): δ 177.2,171.1, 167.0, 150.1, 132.5, 129.2, 127.9, 125.6, 122.6, 83.7, 61.9,60.2, 47.2, 39.3, 37.5, 36.2, 27.4, 23.5, 20.8, 17.6.

Example 51 Synthesis ofS-(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl)ethanethioate (51)

Step 1: Synthesis of S-(4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl)ethanethioate (51a)

A solution of freshly distilled sulfuryl chloride (271 μL, 3.7 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of S-(4-hydroxy-3,3-dimethylbutyl) ethanethioate (preparedaccording to Chem. Commun. 2011, 47, 2038) (500 mg, 2.8 mmol) andpyridine (267 μL, 3.3 mmol) in Et₂O (3 mL) was added dropwise to thesulfuryl chloride solution over the course of 5 min. The flask wasrinsed with diethyl ether (2×5 mL) and the rinse was also added to thereaction mixture. The mixture was stirred at −78° C. for 1 h and allowedto warm to room temperature and stirred at room temperature for another20 min. The precipitate was filtered (quickly) and the filter cakerinsed with Et₂O (12 mL). The filtrate was concentrated under vacuum atroom temperature to afford the title compound (51a) as an oil which wasused immediately for the next step without further purification.

Step 2: Synthesis ofS-(4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl)ethanethioate (51)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (430 mg, 2.3 mmol) was dissolved in pyridine (8 mL) and cooled to 0°C. under an atmosphere of argon. A solution ofS-(4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl) ethanethioate (51a) (0.75g, 2.7 mmol) in THF (4 mL) was added to the reaction mixture at 0° C.The resulting mixture was stirred for 1 h and the solvents were removedunder high vacuum at room temperature. The residue was purified bycolumn chromatography on silica gel using EtOAc/hexanes (0:1 to 9:1) aseluent to afford the product (50) as a solid. LCMS: m/z=424.2 [M+1]+. ¹HNMR (300 MHz, CDCl₃): δ 6.47 (br. s, 1H), 5.61 (br. s, 1H), 4.53 (d,J=8.7 Hz, 1H), 4.24 (d, J=9.0 Hz, 1H), 4.17 (br. s, 1H), 4.05-4.03 (m,1H), 3.39-3.30 (m, 1H), 3.01 (d, J=9.0 Hz, 1H), 2.85-2.80 (m, 2H),2.48-2.40 (m, 1H), 2.32 (s, 3H), 2.20-2.18 (m, 1H), 2.01-1.80 (m, 2H),1.03 (s, 6H). ¹³C NMR (75 MHz, CDCl₃): δ 195.4, 170.9, 166.9, 83.1,61.8, 60.0, 47.1, 38.4, 34.8, 30.5, 23.9, 23.4, 23.2, 20.6, 17.4.

Example 52 Synthesis ofS-(5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl)ethanethioate (52)

Step 1: Synthesis of 5-bromo-2,2-dimethylpentan-1-ol (52a)

DCM (18 mL) was added to LiBH₄ (0.66 g, 30.4 mmol) followed by dropwiseaddition of anhydrous MeOH (1.2 ml, 30.4 mmol) over 20 min under anatmosphere of argon. After the H₂ effervescence had ceased, a solutionof ethyl 5-bromo-2,2-dimethylpentanoate (prepared according to PCTApplication Publication No. 2011046771) (4.5 g, 19.0 mmol) in DCM (10mL) was added dropwise over 20 min. The reaction mixture was heated toreflux for 16 h, cooled to room temperature, and carefully hydrolyzedwith a saturated NH₄Cl solution (30 mL). The suspension was extractedwith DCM (3×50 mL). The combined organic layers were washed with 1N HCl(26 mL) and brine (40 mL), dried, and concentrated under vacuum to givethe product (52a) (3.61 g, 97%) as an oil. ¹H NMR (300 MHz, CDCl₃): δ3.39 (t, J=6.9 Hz, 2H), 3.24 (s, 2H), 1.90-1.76 (m, 2H), 1.48 (br. s,1H), 1.41-1.36 (m, 2H), 0.88 (s, 6H).

Step 2: Synthesis of S-(5-hydroxy-4,4-dimethylpentyl) ethanethioate(52b)

A solution of 5-bromo-2,2-dimethylpentan-1-ol (52a) (2.0 g, 10.3 mmol)and potassium thioacetate (2.34 g, 20.5 mmol) in acetone (22 mL) wasstirred under an inert atmosphere at room temperature for 23 h. Afterremoving the solvents under vacuum at room temperature, the residue waspurified by column chromatography on silica gel column usingEtOAc/hexanes (0:1 to 2:3) as eluent to give the product (52b) (1.2 g,61%) as an oil. ¹H NMR (300 MHz, CDCl₃): δ 3.31 (s, 2H), 2.85 (t, J=7.8Hz, 2H), 2.32 (s, 3H), 1.62-1.48 (m, 2H), 1.32-1.21 (m, 2H), 0.86 (s,6H).

Step 3: Synthesis of S-(5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl)ethanethioate (52c)

A solution of freshly distilled sulfuryl chloride (379 μL, 5.2 mmol) inEt₂O (8 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of S-(5-hydroxy-4,4-dimethylpentyl) ethanethioate (52b) (700mg, 3.6 mmol) and pyridine (374 μL, 4.6 mmol) in Et₂O (4 mL) was addeddropwise to the sulfuryl chloride solution over the course of 5 min. Themixture was stirred at −78° C. for 1 h, and then allowed to warm to roomtemperature. The precipitate was filtered (quickly) and the filter cakerinsed with Et₂O (10 mL). The filtrate was concentrated under vacuum atroom temperature to afford the title compound (52c) as an oil which wasused immediately for the next step without further purification.

Step 4: Synthesis ofS-(5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl)ethanethioate (52)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (600 mg, 3.2 mmol) was dissolved in pyridine (9 mL) and cooled to 0°C. under an atmosphere of argon. A solution ofS-(5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl) ethanethioate (52c) (857mg, 3.0 mmol) in THF (5 mL) was added to the reaction mixture at 0° C.The resulting mixture was stirred for 1 h and the solvents were removedunder high vacuum at room temperature. The residue was purified bycolumn chromatography on silica gel using EtOAc/hexanes (0:1 to 9:1) aseluent to afford the product (52) (70 mg, 5%) as a solid. LC-MS:m/z=438.2 [MH]⁺. ¹H NMR (300 MHz, CDCl₃): δ 6.48 (br. s, 1H), 5.56 (br.s, 1H), 4.49 (d, J=9.0 Hz, 1H), 4.19 (d, J=9.6 Hz, 1H), 4.17 (br. s,1H), 4.05-4.03 (m, 1H), 3.38-3.30 (m, 1H), 3.01 (d, J=9.0 Hz, 1H), 2.85(t, J=6.9 Hz, 2H), 2.46-2.40 (m, 1H), 2.32 (s, 3H), 2.21-2.18 (m, 1H),1.98-1.82 (m, 2H), 1.40-1.33 (m, 2H), 0.97 (s, 3H), 0.96 (s, 3H). ¹³CNMR (75 MHz, CDCl₃): δ 175.7, 170.8, 166.9, 83.6, 61.8, 60.0, 47.1,37.4, 34.3, 30.6, 29.4, 23.9, 23.6, 23.4, 20.6, 17.4.

Example 53 Synthesis ofS-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (53)

Step 1: Synthesis of S-(3-hydroxy-2,2-dimethylpropyl) ethanethioate(53a)

Potassium thioacetate (4.1 g, 35.8 mmol) was dissolved in DMF (20 mL)under an atmosphere of argon. 3-Hydroxy-2,2-dimethylpropyl4-methylbenzenesulfonate (prepared according to PCT ApplicationPublication No. 2012165648) (4.2 g, 16.3 mmol) was added, and themixture was stirred at 80° C. for 2.5 h. After cooling, brine (100 mL)was added, and the mixture was extracted with Et₂O (3×100 mL). Thecombined organic layers were washed with brine (5×50 mL), dried(Na₂SO₄), filtered, and concentrated under vacuum (residual DMF wasremoved by high vacuum). The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 15:85) aseluent to provide the product (53a) (1.06 g, 40%) as an oil. ¹H NMR (300MHz, CDCl₃): δ 3.23 (br. s, 2H), 2.89 (s, 2H), 2.62 (br. s, 1H), 2.37(s, 3H), 0.94 (s, 6H).

Step 2: Synthesis of S-(3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (53b)

A solution of freshly distilled sulfuryl chloride (283 μL, 3.9 mmol) inEt₂O (4 mL) was cooled to −78° C. under an argon atmosphere. A solutionof S-(3-hydroxy-2,2-dimethylpropyl) ethanethioate (53a) (520 mg, 3.1mmol) and pyridine (327 μL, 4.0 mmol) in Et₂O (6 mL) was added dropwiseto the sulfuryl chloride solution over the course of 5 min. The mixturewas stirred at −78° C. for 1 h, then allowed to warm to roomtemperature. The precipitate was filtered (quickly) and the filter cakerinsed with Et₂O (10 mL). The filtrate was concentrated under vacuum atroom temperature to afford the title compound (53b) as an oil which wasused immediately for the next step without further purification.

Step 3: Synthesis ofS-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (53)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (600 mg, 3.2 mmol) was dissolved in pyridine (10 mL) and cooled to0° C. under an atmosphere of argon. A solution ofS-(5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl) ethanethioate (53b) (800mg, 3.1 mmol) in THF (6 mL) was added to the reaction mixture at 0° C.The resulting mixture was stirred for 2 h and the solvents were removedunder high vacuum at room temperature. The residue was purified bycolumn chromatography on silica gel using EtOAc/hexanes (0:1 to 7:3) aseluent to afford the product (53) (90 mg, 7%) as a solid. LCMS:m/z=410.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 6.47 (br. s, 1H), 5.56 (br.s, 1H), 4.51 (d, J=9.3 Hz, 1H), 4.25 (d, J=9.6 Hz, 1H), 4.17 (br. s,1H), 4.06-4.03 (m, 1H), 3.36-3.24 (m, 1H), 3.06-2.88 (m, 2H), 2.51-2.41(m, 1H), 2.36 (s, 3H), 2.21-2.08 (m, 1H), 1.98-1.82 (m, 2H), 1.36-1.22(m, 1H), 1.04 (s, 3H), 1.02 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 194.7,170.8, 166.9, 81.9, 61.8, 60.1, 47.1, 36.7, 35.6, 30.6, 23.2, 22.9,20.6, 17.4.

Example 54 Synthesis of3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl2,6-dimethylbenzoate (54)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl 2,6-dimethylbenzoate(54a)

To a stirred solution of 2,2-dimethylpropane-1,3-diol (2.5 g, 24.3 mmol)in DCM (60 mL) at ca. 0° C. (ice bath) under an atmosphere of argon, wasadded 2,6-dimethylbenzoyl chloride (1.2 mL, 8.1 mmol), pyridine (1.1 mL,13.7 mmol), and N,N-4-dimethylaminopyridine (99 mg, 0.8 mmol). Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred overnight. The reaction was quenched by theaddition of 1N HCl, and the mixture was extracted with DCM (twice). Thecombined organic extracts were washed with a saturated aqueous solutionof NaHCO₃ and brine, dried (MgSO₄), filtered and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (1:9 to 2:3) as eluent to give the product (54a)(1.5 g, 78%) as an oil. ¹H NMR (300 MHz, CDCl₃): δ 7.21 (m, 1H), 7.04(m, 2H), 4.18 (s, 2H), 3.41 (s, 2H), 2.32 (s, 6H), 2.20 (br. s, 1H),0.99 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl2,6-dimethylbenzoate (54b)

A solution of freshly distilled sulfuryl chloride (0.25 mL, 3.9 mmol) inEt₂O (6 mL) was cooled to −78° C. under an argon atmosphere. A solutionof 3-hydroxy-2,2-dimethylpropyl 2,6-dimethylbenzoate (54a) (500 mg, 2.1mmol) and pyridine (0.26 mL, 3.3 mmol) in Et₂O (6 mL) was added dropwiseto the sulfuryl chloride solution over the course of 5 min. The mixturewas stirred at −78° C. for 1 h, and then allowed to warm to roomtemperature. The precipitate was filtered (quickly) and the filter cakerinsed with Et₂O (12 mL). The filtrate was concentrated under vacuum atroom temperature to afford the title compound (54b) as an oil, which wasused immediately in the next step without further purification.

Step 3: Synthesis of3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl2,6-dimethylbenzoate (54)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (420 mg, 2.3 mmol) was dissolved in THF (12 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (0.7 mL), and the resultingsolution was cooled to −78° C. under an argon atmosphere. A solution ofNaHMDS, 1.0 M in THF (2.3 mL, 2.3 mmol) was added dropwise to the cooledsolution and stirred for 10 min. A solution of3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl 2,6-dimethylbenzoate (54b)(660 mg, 2.0 mmol) in THF (8 mL) was added quickly to the reactionmixture. After stirring at −78° C. for 10 min, the mixture was allowedto warm to room temperature and stirred for 2 h. EtOAc (400 mL), andsaturated aqueous NaHCO₃ (40 mL) and water (40 mL) were added. Theorganic layer was separated and washed with saturated aqueous NaHCO₃ (60mL), H₂O (3×50 mL), brine (60 mL), and then dried (Na₂SO₄), andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 7:3) as eluentto give the product (180 mg, 19%) as a solid. LC-MS: m/z=484.01 [M+H]⁺.¹H NMR (300 MHz, CDCl₃): δ 7.19 (m, 1H), 7.04 (m, 2H), 6.47 (s, 1H),5.55 (s, 1H), 4.58 (d, J=9.3 Hz, 1H), 4.39 (d, J=9.0 Hz, 1H), 4.22 (d,J=11.1 Hz, 1H), 4.16 (m, 1H), 4.11 (d, J=11.1 Hz, 1H), 4.04-4.02 (m,1H), 3.33-3.29 (m, 1H), 3.01-2.98 (m, 1H), 2.45-2.40 (m, 1H), 2.32 (s,6H), 2.20-2.08 (m, 1H), 1.93-1.76 (m, 2H), 1.10 (s, 6H). ¹³C NMR (75MHz, CDCl₃): δ 170.8, 169.9, 166.9, 134.9, 133.6, 129.4, 127.5, 80.2,69.1, 61.8, 60.1, 47.1, 35.2, 21.4, 21.3, 20.7, 19.8, 17.4.

Example 55 Synthesis of3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyladamantane-1-carboxylate (55)

Step 1: Synthesis of 3-hydroxy-2,2-dimethylpropyl(3r,5r,7r)-adamantane-1-carboxylate (55a)

To a stirred solution of 2,2-dimethylpropane-1,3-diol (2.5 g, 24.3 mmol)in DCM (60 mL) at ca. 0° C. (ice bath) under an argon atmosphere, wasadded 1-adamantane-carbonyl chloride (1.36 g, 6.9 mmol), pyridine (1.1mL, 13.7 mmol), and N,N-4-dimethylaminopyridine (99 mg, 0.8 mmol). Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred overnight. The reaction was quenched by theaddition of 1N HCl, and the mixture was extracted with DCM (twice). Thecombined organic extracts were washed with a saturated aqueous solutionof NaHCO₃ and brine, dried (MgSO₄), filtered, and concentrated undervacuum to give the product (55a) (1.82 g, 100%) as an oil. ¹H NMR (300MHz, CDCl₃): δ 3.91 (s, 2H), 3.25 (s, 2H), 2.01 (br. s, 3H), 1.89 (br.s, 6H), 1.71 (br. s, 7H), 0.91 (s, 6H).

Step 2: Synthesis of 3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl(3r,5r,7r)-adamantane-1-carboxylate (55b)

A solution of freshly distilled sulfuryl chloride (266 μL, 3.3 mmol) inEt₂O (4 mL) was cooled to −78° C. under an argon atmosphere. A solutionof 3-hydroxy-2,2-dimethylpropyl-adamantane-1-carboxylate (55a) (600 mg,2.2 mmol) and pyridine (0.28 mL, 3.5 mmol) in Et₂O (4 mL) was addeddropwise to the sulfuryl chloride solution over the course of 5 min. Theflask was rinsed with Et₂O (5 mL), and the rinse was also added to thereaction mixture. The mixture was stirred at −78° C. for 1 h, and thenallowed to warm to room temperature. The precipitate was filtered(quickly) and the filter cake rinsed with Et₂O (12 mL). The filtrate wasconcentrated under vacuum at room temperature to afford the titlecompound (55b) as an oil, which was used immediately in the next stepwithout further purification.

Step 3: Synthesis of3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyladamantane-1-carboxylate (55)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (442 mg, 2.4 mmol) was dissolved in THF (14 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (0.8 mL), and the resultingsolution was cooled to −78° C. under an argon atmosphere. A solution ofNaHMDS, 1.0 M in THF (2.6 mL, 2.6 mmol) was added dropwise to the cooledsolution and stirred for 10 min. A solution of3-((chlorosulfonyl)oxy)-2,2-dimethylpropyl-adamantane-1-carboxylate(55b) (750 mg, 2.1 mmol) in THF (8 mL) was quickly added to the reactionmixture. After stirring at −78° C. for 10 min, the mixture was allowedto warm to room temperature and stirred for 2 h. EtOAc (400 mL) andsaturated aqueous NaHCO₃ (40 mL) and H₂O (40 mL) were added. The organiclayer was separated and washed with saturated aqueous NaHCO₃ (60 mL),H₂O (3×50 mL), brine (60 mL), then dried (Na₂SO₄), and concentratedunder vacuum. The residue was purified by column chromatography onsilica gel using EtOAc/hexanes (0:1 to 7:3) as eluent to give theproduct (55) (180 mg, 17%) as a solid. LC-MS: m/z=514.12 [M+H]⁺. ¹H NMR(300 MHz, CDCl₃): δ 6.48 (s, 1H), 5.55 (s, 1H), 4.58 (d, J=8.7 Hz, 1H),4.36 (d, J=9.3 Hz, 1H), 4.17 (m, 1H), 4.05 (d, J=6.9 Hz, 1H), 3.93 (d,J=11.1 Hz, 1H), 3.84 (d, J=11.1 Hz, 1H), 3.34-3.32 (m, 1H), 3.03-2.99(m, 1H), 2.49-2.41 (m, 1H), 2.20-2.14 (m, 1H), 2.04 (br. s, 3H),1.91-1.8 (m, 8H), 1.87 (br. s, 6H), 1.03 (s, 7H). ¹³C NMR (75 MHz,CDCl₃): δ 178.0, 171.7, 167.7, 81.3, 68.7, 62.6, 60.8, 47.8, 41.6, 39.5,37.2, 36.2, 28.6, 22.0, 21.9, 21.4, 18.1.

Example 56 Synthesis of diethyl2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate(56)

Step 1: Synthesis of diethyl 2-(hydroxymethyl)-2-methylmalonate (56a)

To a suspension of paraformaldehyde (1.3 g, 43.3 mmol) and K₂CO₃ (11 g,79 mmol) in EtOH (150 mL) was added diethyl 2-methylmalonate (4.5 mL,26.3 mmol). The mixture was stirred at room temperature for 17 h, thenfiltered through a pad of Celite®, and the filter cake washed with EtOH(2×30 mL). The filtrate was concentrated under vacuum and the residuewas purified by column chromatography on silica gel using EtOAc/hexanes(0:1 to 3:2) as eluent to afford the product (56a) (4.0 g, 74%) as anoil. ¹H NMR (300 MHz, CDCl₃): δ 4.22 (q, J=6.9 Hz, 4H), 3.83 (d, J=6.9Hz, 2H), 2.90 (t, J=7.8 Hz, 1H), 1.42 (s, 3H), 1.26 (t, J=6.9 Hz, 6H).

Step 2: Synthesis of diethyl2-(((chlorosulfonyl)oxy)methyl)-2-methylmalonate (56b)

A solution of freshly distilled sulfuryl chloride (248 μL, 3.0 mmol) inEt₂O (8 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of diethyl 2-(hydroxymethyl)-2-methylmalonate (56a) (500 mg,2.4 mmol) and pyridine (0.26 mL, 3.2 mmol) in Et₂O (4 mL) was addeddropwise to the sulfuryl chloride solution over the course of 5 min. Theflask was rinsed with Et₂O (5 mL), and the rinse was also added to thereaction mixture. The mixture was stirred at −78° C. for 1 h, and thenallowed to warm to room temperature. The precipitate was filtered(quickly) and the filter cake rinsed with Et₂O (12 mL). The filtrate wasconcentrated under vacuum at room temperature to afford the titlecompound (56b) as an oil which was used immediately in the next stepwithout further purification.

Step 3: Synthesis of diethyl2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylmalonate(56)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (390 mg, 2.1 mmol) was dissolved in THF (10 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (0.8 mL), and the resultingsolution was cooled to −78° C. under an argon atmosphere. A solution ofNaHMDS, 1.0 M in THF (2.2 mL, 2.2 mmol) was added dropwise to the cooledsolution and stirred for 10 min. A solution of diethyl2-(((chlorosulfonyl)oxy)methyl)-2-methylmalonate (56b) (638 mg, 2.1mmol) in THF (8 mL) was quickly added to the reaction mixture. Afterstirring at −78° C. for 10 min, the mixture was allowed to warm to roomtemperature and stirred for 2 h. EtOAc (400 mL) and saturated aqueousNaHCO₃ (40 mL) and H₂O (40 mL) were added. The organic layer wasseparated and washed with saturated aqueous NaHCO₃ (60 mL), H₂O (3×50mL), brine (60 mL), then dried (Na₂SO₄), and concentrated under vacuum.The residue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 9:1) as eluent to give the product (56) (166 mg,17%) as a solid. LC-MS: m/z=452.03 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ6.49 (s, 1H), 5.58 (s, 1H), 5.02 (d, J=8.7 Hz, 1H), 4.93 (d, J=9.3 Hz,1H), 4.24 (q, J=7.2 Hz, 4H), 4.17 (m, 1H), 4.05 (d, J=6.9 Hz, 1H), 3.35(m, 1H), 3.01 (d, J=11.1 Hz, 1H), 2.49-2.41 (m, 1H), 2.20-2.14 (m, 1H),1.98-1.81 (m, 2H), 1.56 (s, 3H), 1.28 (t, J=7.2 Hz, 6H). ¹³C NMR (75MHz, CDCl₃): δ 171.1, 168.6, 168.5, 167.1, 76.5, 62.3, 61.9, 60.2, 53.9,47.1, 20.8, 17.8, 17.5, 14.0.

Example 57 Synthesis of propyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(57)

Step 1: Synthesis of propyl 3-hydroxy-2,2-dimethylpropanoate (57a)

A mixture of 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol) wascharged and 1-propanol (15 mL) and conc. H₂SO₄ (70 μL, 1.3 mmol) in a 20mL-microwave vial was stirred at room temperature and then heated in amicrowave at 80° C. for 2 h, and stirred at room temperature overnight.When the desired product was identified by TLC (EtOAc/hexanes; 3:7) themixture was concentrated under vacuum (40° C.) and diluted with EtOAc(80 mL) and H₂O (30 mL). The organic layer was washed with H₂O (twice),and brine, then dried (Na₂SO₄), filtered, and concentrated to give theproduct (57a) (1.18 g, 76%) as an oil. The material was used next stepdirectly without purification. ¹H NMR (300 MHz, CDCl₃): δ 4.07 (t, J=6.6Hz, 2H), 3.55 (s, 2H), 2.42 (br. s, 1H), 1.70-1.61 (m, 2H), 1.19 (s,6H), 0.95 (t, J=7.5 Hz, 3H).

Step 2: Synthesis of propyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (57b)

A solution of freshly distilled sulfuryl chloride (194 μL, 2.7 mmol) inEt₂O (1.0 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of propyl 3-hydroxy-2,2-dimethylpropanoate (57a) (0.42 g, 2.6mmol) and pyridine (215 μL, 2.7 mmol) in Et₂O was added dropwise to thesulfuryl chloride solution over the course of 5 min. The flask wasrinsed with Et₂O (3×1 mL), and the rinse was added to the reactionmixture. The mixture was stirred at −78° C. for 5 min and then allowedto warm to room temperature and stirred for 1 h. The mixture wasfiltered and the filtrate was concentrated under vacuum to afford thetitle compound (57b) (0.56 g, 83%) as an oil, which was used immediatelyin the next step without further purification. ¹H NMR (300 MHz, CDCl₃):δ 4.50 (s, 2H), 4.10 (t, J=6.6 Hz, 2H), 1.72-1.64 (m, 2H), 1.32 (s, 6H),0.95 (t, J=7.2 Hz, 3H).

Step 3: Synthesis of propyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(57)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.22 g, 1.2 mmol) was dissolved in THF (5.5 mL) and HMPA (1.0 mL),and the resulting stirred solution was cooled to −78° C. under anatmosphere of argon. A solution of NaHMDS, 1.0 M in THF (1.5 mL, 1.5mmol) was added to the mixture, and then a solution of propyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (57b) (0.40 g, 1.5 mmol)in THF (2×1 mL) was quickly added to the reaction mixture. After 10 minstirring at −78° C., the mixture was allowed to warm to room temperatureand stirred for 1 h. The mixture was quenched with H₂O and diluted withEtOAc (40 mL). The aqueous and organic layers were separated and theorganic layer was washed with brine, dried (Na₂SO₄), and concentratedunder vacuum. The residue was purified by column chromatography onsilica gel using EtOAc/hexanes (3:7 to 1:0) as eluent to give thedesired product (57) (190 mg, 39%) as a solid. LCMS: m/z=408.1 [M+H]⁺.¹H NMR (300 MHz, CDCl₃): δ 6.47 (br. s, 1H), 5.57 (br. s, 1H), 4.66 (dd,J=9.0, 35.1 Hz, 2H), 4.17-4.04 (m, 4H), 3.32 (d, J=12.3 Hz, 1H), 3.02(d, J=10.8 Hz, 1H), 2.46-2.41 (m, 1H), 2.14-2.13 (m, 1H), 1.99-1.83 (m,2H), 1.71-1.66 (m, 2H), 1.29 (s, 3H), 1.28 (s, 3H), 0.95 (t, J=7.6 Hz,3H). ¹³C NMR (75 MHz, CDCl₃): δ 174.1, 170.9, 166.8, 80.3, 66.8, 61.8,60.1, 47.1, 42.9, 22.1, 21.9, 21.6, 20.7, 17.4, 10.3.

Example (58) Synthesis of butyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(58)

Step 1: Synthesis of butyl 3-hydroxy-2,2-dimethylpropanoate (58a)

A mixture of 3-hydroxy-2,2-dimethylpropanoic acid (1.15 g, 9.7 mmol) wascharged and 1-butanol (15 mL) and conc. H₂SO₄ (70 μL, 1.3 mmol) in a 20mL-microwave vial was stirred at room temperature then heated in amicrowave at 80° C. for 2 h, then stirred at room temperature overnight.When the desired product was identified by TLC (EtOAc/hexanes; 3:7) themixture was concentrated under vacuum (40° C.; co-evaporated withtoluene×3) and diluted with EtOAc (80 mL) and H₂O (30 mL). The organiclayer was washed with H₂O (twice), and brine, then dried (Na₂SO₄),filtered and concentrated to give the product (58a) (1.24 g, 81%) as anoil. The material was used next step directly without purification. ¹HNMR (300 MHz, CDCl₃): δ 4.11 (t, J=6.5 Hz, 2H), 3.55 (s, 2H), 2.42 (br.s, 1H), 1.65-1.58 (m, 2H), 1.43-1.35 (m, 2H), 1.19 (s, 6H), 0.94 (t,J=7.5 Hz, 3H).

Step 2: Synthesis of butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (58b)

A solution of freshly distilled sulfuryl chloride (198 μL, 2.7 mmol) inEt₂O (1.0 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of propyl 3-hydroxy-2,2-dimethylpropanoate (58a) (0.47 g, 2.7mmol) and pyridine (219 μL, 2.7 mmol) in Et₂O was added dropwise to thesulfuryl chloride solution over the course of 5 min. The flask wasrinsed with Et₂O (3×1 mL), which was added to the reaction mixture. Themixture was stirred at −78° C. for 5 min and then allowed to warm toroom temperature and stirred for 1 h. The mixture was filtered, and thefiltrate was concentrated under vacuum to afford the title compound(58b) (0.52 g, 72%) as an oil, which was used immediately in the nextstep without further purification. ¹H NMR (300 MHz, CDCl₃): δ 4.50 (s,2H), 4.14 (t, J=6.8 Hz, 2H), 1.66-1.59 (m, 2H), 1.43-1.35 (m, 2H), 1.32(s, 6H), 0.94 (t, J=7.4 Hz, 3H).

Step 3: Synthesis of butyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(58)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.22 g, 1.2 mmol) was dissolved in THF (5 mL) and HMPA (1 mL), andthe resulting stirred solution was cooled to −78° C. under an argonatmosphere. A solution of NaHMDS, 1.0 M in THF (1.5 mL, 1.5 mmol) wasadded, and the mixture stirred for 10 min. A solution of butyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (58b) (0.41 g, 1.5 mmol)in THF (5×1 mL) was quickly added to the reaction mixture. After 10 minstirring at −78° C., the mixture was allowed to warm to room temperatureand stirred for 1 h. The mixture was quenched with H₂O and diluted withEtOAc (40 mL). The aqueous and organic layers were separated, and theorganic layer was washed with brine, dried (Na₂SO₄), and concentratedunder vacuum. The residue was dissolved in DMF and purified bypreparative HPLC to give the desired product (58) (70 mg, 14%) as asolid. LCMS: m/z=422.2 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 6.47 (br. s,1H), 5.67 (br. s, 1H), 4.65 (dd, J=34.8, 9.0 Hz, 2H), 4.16-4.04 (m, 4H),3.32 (d, J=11.7 Hz, 1H), 3.02 (d, J=12.3 Hz, 1H), 2.47-2.40 (m, 1H),2.18-2.13 (m, 1H), 2.01-1.80 (m, 2H), 1.67-1.58 (m, 3H), 1.45-1.32 (m,2H), 1.28 (s, 3H), 1.27 (s, 3H), 0.94 (t, J=7.4 Hz, 3H). ¹³C NMR (75MHz, CDCl₃): δ 174.1, 170.8, 166.8, 80.3, 65.1, 61.8, 60.1, 47.1, 42.8,30.5, 22.1, 21.6, 20.7, 19.0, 17.4, 13.6.

Example 59 Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(59)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.22 g, 1.2 mmol) was dissolved in THF (10 mL) and HMPA (0.5 mL),and the resulting stirred solution was cooled to −78° C. under anatmosphere of argon. A solution of NaHMDS, 1.0 M in THF (1.3 mL, 1.3mmol) was added to the mixture, and the mixture stirred for 10 min. Asolution of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (0.42 g, 1.3 mmol) in THF(5×1 mL) was quickly added to the reaction mixture. After 10 minstirring at −78° C., the mixture was allowed to warm to room temperatureand stirred for 1 h. The mixture was cooled to 0° C. and quenched withH₂O and diluted with EtOAc (40 mL). The aqueous and organic layers wereseparated, and the organic layer was washed with brine, dried (Na₂SO₄),and concentrated under vacuum. The residue was purified by preparativeHPLC to give the desired product (59) (189 mg, 34%) as a solid. LCMS:m/z=478.1 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 6.68 (br. s, 1H), 5.74 (br.s, 1H), 4.95-4.79 (m, 3H), 4.50 (d, J=9.3 Hz, 1H), 4.14 (br. s, 1H),4.03 (d, J=7.2 Hz, 1H), 3.32 (d, J=12.3 Hz, 1H), 3.02 (d, J=12.3 Hz,1H), 2.45-2.39 (m, 1H), 2.17-2.09 (m, 4H), 1.98-1.79 (m, 2H), 1.30 (s,3H), 1.29 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 177.6, 171.0, 167.0,152.2, 140.5, 133.2, 80.0, 61.8, 60.2, 54.4, 47.0, 43.0, 21.8, 21.7,20.7, 17.5, 9.3.

Example 60 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutylpivalate (60)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl pivalate (60a)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (0.86 g, 7.3 mmol)in DCM (9 mL) at ca. 0° C. (ice bath) under an argon atmosphere, wasadded trimethylacetyl chloride (0.89 mL, 7.3 mmol), Et₃N (1.17 mL, 14.5mmol), and N,N-4-dimethylaminopyridine (catalytic amount). The reactionmixture was allowed to gradually warm to room temperature and themixture was stirred overnight. The mixture was quenched by the additionof 1N HCl (50 mL). The organic and aqueous layers were partitioned andthe aqueous layer was extracted with DCM (twice). The combined organiclayers were washed with saturated NaHCO₃ and brine, then dried (Na₂SO₄),and concentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 3:7) as eluentto give the desired product (60a) (0.42 g, 28%). ¹H NMR (300 MHz,CDCl₃): δ 4.13 (t, J=7.1 Hz, 2H), 3.35 (s, 2H), 1.61 (q, J=6.9 Hz, 2H),1.19 (s, 9H), 0.93 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl pivalate(60b)

A solution of freshly distilled sulfuryl chloride (153 μL, 2.1 mmol) inEt₂O (4.5 mL) was cooled to −78° C. under an argon atmosphere. Asolution of 4-hydroxy-3,3-dimethylbutyl pivalate (60a) (0.42 g, 2.1mmol) and pyridine (203 μL, 2.5 mmol) in Et₂O (3 mL) was added dropwiseto the sulfuryl chloride solution over the course of 60 min. The mixturewas allowed to warm to room temperature and stirred for 30 min. Themixture was filtered, and the filtrate was concentrated under vacuum toafford the title compound (60b) as an oil, which was used immediately inthe next step without further purification. ¹H NMR (300 MHz, CDCl₃): δ4.23 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 1.71 (t, J=6.6 Hz, 2H), 1.19 (s,9H), 1.08 (s, 6H).

Step 3: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutylpivalate (60)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.41 g, 2.2 mmol) was dissolved in THF (18.5 mL) and HMPA (0.9 mL),and the resulting stirred solution was cooled to −78° C. under anatmosphere of argon. A solution of NaHMDS, 1.0 M in THF (2.2 mL, 2.2mmol) was added to the mixture, and the mixture stirred for 10 min. Asolution of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl pivalate (60b)(0.73 g, 2.4 mmol) in THF (20 mL) was quickly added to the reactionmixture. After 10 min stirring at −78° C., the mixture was allowed towarm to room temperature and stirred for 16 h. The mixture was quenchedwith H₂O and diluted with EtOAc. The aqueous and organic layers wereseparated, and the organic layer was washed with brine, dried (Na₂SO₄),and concentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 1:0) as eluentto give the product (60) (176 mg) as a solid. LCMS: m/z=450.15 [M+H]⁺.¹H NMR (300 MHz, CDCl₃): δ 6.49 (br. s, 1H), 5.59 (br. s, 1H), 4.55 (d,J=9.3 Hz, 1H), 4.26-4.04 (m, 5H), 3.34 (d, J=11.7 Hz, 1H), 3.02 (d,J=12.3 Hz, 1H), 2.45-2.41 (m, 1H), 2.19-2.15 (m, 1H), 2.01-1.85 (m, 2H),1.69 (t, J=6.8 Hz, 2H), 1.19 (s, 9H), 1.05 (s, 6H). ¹³C NMR (75 MHz,CDCl₃): δ178.6, 171.0, 167.0, 83.8, 61.9, 60.8, 60.2, 47.2, 38.7, 36.9,34.0, 27.2, 24.0, 23.7, 20.8, 17.5.

Example 61 Synthesis of ethyl2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate(61)

Step 1: Synthesis of ethyl2-(((chlorosulfonyl)oxy)methyl)-2-ethylbutanoate (61a)

A solution of freshly distilled sulfuryl chloride (126 μL, 1.7 mmol) inEt₂O (3.2 mL) was cooled to −78° C. under an argon atmosphere. Asolution of ethyl 2-ethyl-2-(hydroxymethyl)butanoate (ex-enamine) (0.30g, 1.7 mmol) and pyridine (153 μL, 1.9 mmol) in Et₂O (2.1 mL) was addeddropwise to the sulfuryl chloride solution over the course of 60 min.The mixture was allowed to warm to room temperature and stirred for 30min. The mixture was re-cooled to −78° C. and sulfuryl chloride (20 μL)was added, and the reaction allowed to warm to room temperature andstirred for a further 30 min. Et₂O (5 mL) was added and the mixturestirred for 5 min, then filtered, and the filtrate was concentratedunder vacuum to afford the title compound (61a), which was usedimmediately in the next step without further purification. ¹H NMR (300MHz, CDCl₃): δ 4.62 (s, 2H), 4.21 (q, J=7.3 Hz, 2H), 1.78-1.58 (m, 4H),1.28 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.7 Hz, 6H).

Step 2: Synthesis of ethyl2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate(61)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.25 g, 1.4 mmol) was dissolved in THF (11.2 mL) and HMPA (0.6 mL),and the resulting stirred solution was cooled to −78° C. under anatmosphere of argon. A solution of NaHMDS, 1.0 M in THF (1.4 mL, 1.4mmol) was added to the mixture, and the mixture stirred for 10 min. Asolution of ethyl 2-(((chlorosulfonyl)oxy)methyl)-2-ethylbutanoate (61a)(0.41 g, 1.5 mmol) in THF (20 mL) was quickly added to the reactionmixture. After 10 min stirring at −78° C., the mixture was allowed towarm to room temperature and stirred for 16 h. The mixture was quenchedwith H₂O and diluted with EtOAc. The aqueous and organic layers wereseparated, and the organic layer was washed with brine, dried (Na₂SO₄),and concentrated under vacuum. The residue was purified by columnchromatography on silica gel to give the product (61) (162 mg, 29%) as asolid. LCMS: m/z=422.03 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 6.50 (br. s,1H), 5.66 (br. s, 1H), 4.87 (d, J=9.9 Hz, 1H), 4.70 (d, J=9.9 Hz, 1H),4.22-4.14 (m, 3H), 4.06 (d, J=7.2 Hz, 1H), 3.33 (d, J=11.7 Hz, 1H), 3.02(d, J=12.3 H, 1H), 2.47-2.41 (m, 1H), 2.22-2.12 (m, 1H), 2.01-1.60 (m,6H), 1.27 (t, J=7.1 Hz, 3H), 0.92-0.83 (m, 6H). ¹³C NMR (75 MHz, CDCl₃):δ 173.3, 171.1, 167.1, 75.2, 62.0, 61.1, 60.2, 50.6, 47.2, 26.2, 25.8,20.9, 17.5, 14.3, 8.4, 8.3.

Example 62 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethylbenzoate (62)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethylbenzoate(62a)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (0.84 g, 7.1 mmol)in DCM (9 mL) at ca. 0° C. (ice bath) under an argon atmosphere, wasadded 2,6-dimethylbenzoyl chloride (1.0 g, 5.9 mmol), pyridine (0.96 mL,11.9 mmol), and N,N-4-dimethylaminopyridine (catalytic amount). Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred overnight. The mixture was quenched by theaddition of 1N HCl (50 mL). The organic and aqueous layers werepartitioned and the aqueous layer was extracted with DCM (twice). Thecombined organic layers were washed with saturated NaHCO₃, and thendried (Na₂SO₄), and concentrated under vacuum. The residue was purifiedby column chromatography on silica gel using EtOAc/hexanes (0:1 to 3:7)as eluent to give the desired product (62a) (0.42 g, 28%). ¹H NMR (300MHz, CDCl₃): δ 7.18 (t, J=7.6 Hz, 1H), 7.04-7.01 (m, 2H), 4.41 (t, J=7.6Hz, 2H), 3.37 (s, 2H), 2.31 (s, 6H), 1.76 (t, J=7.5 Hz, 2H), 0.97 (s,6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethylbenzoate (62b)

A solution of freshly distilled sulfuryl chloride (122 μL, 1.7 mmol) inEt₂O (1.0 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethylbenzoate (62a) (0.42g, 1.7 mmol) and pyridine (136 μL, 1.7 mmol) in Et₂O (1.5 mL) was addeddropwise to the sulfuryl chloride solution over the course of 15 min.The flask was rinsed with Et₂O (2×20 mL), and the rinse was added to thereaction mixture. The mixture was stirred at −78° C. for 10 min thenallowed to warm to room temperature and stirred for 1 h. The mixture wasfiltered, and the filtrate was concentrated under vacuum to afford thetitle compound (62b) as an oil, which was used immediately in the nextstep without further purification (not pure). ¹H NMR (300 MHz, CDCl₃): δ7.19 (t, J=7.7 Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4.41 (t, J=7.4 Hz, 2H),4.23 (s, 2H), 2.31 (s, 6H), 1.84 (t, J=6.9 Hz, 2H), 1.11 (s, 6H).

Step 3: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethylbenzoate (62)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.22 g, 1.2 mmol) was dissolved in THF (10 mL) and HMPA (0.5 mL),and the resulting stirred solution was cooled to −78° C. under anatmosphere of argon. A solution of NaHMDS, 1.0 M in THF (1.2 mL, 1.2mmol) was added to the mixture, and the mixture stirred for 10 min. Asolution of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethylbenzoate (62b) (0.42 g, 1.2 mmol) in Et₂O (20 mL) wasquickly added to the reaction mixture. After 10 min stirring at −78° C.,the mixture was allowed to warm to room temperature and stirred for 1 h.The mixture was cooled to 0° C. and quenched with H₂O and diluted withEtOAc. The aqueous and organic layers were separated, and the organiclayer was washed with brine, dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 7:3) as eluent to give the product (62) (192mg, 32%) as a solid. LCMS: m/z=498.08 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ7.18 (t, J=7.5 Hz, 1H), 7.02 (d, J=7.5 Hz, 2H), 6.48 (br. s, 1H), 5.63(br. s, 1H), 4.57 (d, J=9.0 Hz, 1H), 4.40 (t, J=7.5 Hz, 2H), 4.25 (d,J=8.7 Hz, 1H), 4.17 (br. s, 1H), 4.04 (d, J=6.3 Hz, 1H), 3.32 (d, J=12.3Hz, 1H), 3.00 (d, J=12.3 Hz, 1H), 2.47-2.40 (m, 1H), 2.31 (s, 6H),2.18-2.14 (m, 1H), 1.97-1.80 (m, 4H), 1.08 (s, 6H). ¹³C NMR (75 MHz,CDCl₃): δ 170.9, 170.0, 167.1, 134.8, 133.8, 129.4, 127.6, 83.4, 61.9,61.3, 60.1, 47.1, 36.7, 33.9, 23.9, 23.6, 20.7, 19.8, 17.4.

Example 63 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyladamantane-1-carboxylate (63)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyladamantane-1-carboxylate (63a)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (0.72 g, 6.1 mmol)in DCM (20 mL) at ca. 0° C. (ice bath) under an atmosphere of argon, wasadded 1-adamantane-carbonyl chloride (1.1 g, 10.1 mmol), pyridine (0.82mL, 10.1 mmol), and N,N-4-dimethylaminopyridine (0.03 g, 0.3 mmol). Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred overnight. The mixture was quenched by theaddition of 1N HCl. The organic and aqueous layers were partitioned, andthe aqueous layer was extracted with DCM (twice). The combined organiclayers were washed with saturated NaHCO₃ and brine, and then dried(MgSO₄), and concentrated under vacuum. The residue was purified bycolumn chromatography on silica gel using EtOAc/hexanes (0:1 to 1:1) aseluent to give the desired product (63a) (0.49 g, 35%). ¹H NMR (300 MHz,CDCl₃): δ 4.14-4.09 (m, 2H), 3.34 (s, 2H), 2.00 (m, 3H), 1.90-1.86 (m,6H), 1.75-1.59 (m, 6H), 1.59 (t, J=7.1 Hz, 2H), 0.92 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyladamantane-1-carboxylate (63b)

A solution of freshly distilled sulfuryl chloride (127 μL, 1.7 mmol) inEt₂O (1.2 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 4-hydroxy-3,3-dimethylbutyl adamantane-1-carboxylate (63a)(0.48 g, 1.7 mmol) and pyridine (141 μL, 1.7 mmol) in Et₂O (1.7 mL) wasadded dropwise to the sulfuryl chloride solution over the course of 15min. The flask was rinsed with Et₂O (2×20 mL), and the rinse was addedto the reaction mixture. The mixture was stirred at −78° C. for 10 minand then allowed to warm to room temperature and stirred for 1 h. Themixture was filtered, and the filtrate was concentrated under vacuum toafford the title compound (63b) as an oil, which was used immediately inthe next step without further purification (not pure). ¹H NMR (300 MHz,CDCl₃): δ 4.25 (s, 2H), 4.13 (t, J=6.8 Hz, 2H), 2.01 (m, 3H), 1.90-1.85(m, 6H), 1.73-1.69 (m, 8H), 1.08 (s, 6H).

Step 3: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyladamantane-1-carboxylate (63)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.22 g, 1.2 mmol) was dissolved in THF (10 mL) and HMPA (0.5 mL),and the resulting stirred solution was cooled to −78° C. under anatmosphere of argon. A solution of NaHMDS, 1.0 M in THF (1.2 mL, 1.2mmol) was added to the mixture, and the mixture stirred for 10 min. Asolution of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyladamantane-1-carboxylate (63b) (0.66 g, 1.7 mmol) in Et₂O (20 mL) wasadded quickly to the reaction mixture. After 10 min stirring at −78° C.,the mixture was allowed to warm to room temperature and stirred for 1 h.The mixture was cooled to 0° C. and quenched with H₂O and diluted withEtOAc. The aqueous and organic layers were separated, and the organiclayer was washed with brine, dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 7:3) as eluent to give a solid, which wastriturated with hexanes to give the product (63) (230 mg, 36%) as asolid. LCMS: m/z=528.17 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.18 (t,J=7.5 Hz, 1H), 7.02 (d, J=7.5 Hz, 2H), 6.48 (br. s, 1H), 5.63 (br. s,1H), 4.57 (d, J=9.0 Hz, 1H), 4.40 (t, J=7.5 Hz, 2H), 4.25 (d, J=8.7 Hz,1H), 4.17 (br. s, 1H), 4.04 (d, J=6.3 Hz, 1H), 3.32 (d, J=12.3 Hz, 1H),3.00 (d, J=12.3 Hz, 1H), 2.47-2.40 (m, 1H), 2.31 (s, 6H), 2.18-2.14 (m,1H), 1.97-1.80 (m, 4H), 1.08 (s, 6H). ¹³C NMR (75 MHz, CDCl₃): δ 177.8,171.0, 167.1, 83.9, 62.0, 60.7, 60.2, 47.2, 40.7, 39.0, 39.0, 37.0,36.6, 34.1, 28.0, 24.0, 23.8, 20.8, 17.5.

Example 64 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethoxybenzoate (64)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethoxybenzoate(64a)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (1.85 g, 15.7 mmol)in DCM (28 mL) at ca. 0° C. (ice bath) under an atmosphere of argon, wasadded 2,6-dimethoxybenzoyl chloride (80%; 3.93 g, 15.7 mmol), Et₃N (2.5mL, 31.3 mmol), and N,N-4-dimethylaminopyridine (catalytic amount). Thereaction mixture was allowed to gradually warm to room temperature andthe mixture was stirred overnight. The mixture was concentrated undervacuum and suspended in EtOAc, and then filtered and the filter cakewashed with EtOAc. The filtrate was concentrated under vacuum and theresidue purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 2:3) as eluent to give the desired product (64a)(ca. 80% purity; 0.92 g). ¹H NMR (300 MHz, CDCl₃): δ 7.29-7.26 (m, 1H),6.57-6.53 (m, 3H), 4.43-4.39 (m, 2H), 3.83 (s, 6H), 3.36 (s, 2H), 1.74(t, J=6.5 Hz, 2H), 0.95 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethoxybenzoate (64b)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.7 mmol) inEt₂O (1.9 mL) was cooled to −78° C. under an argon atmosphere. Asolution of 4-hydroxy-3,3-dimethylbutyl 2,6-dimethoxybenzoate (64a) (ca.80% purity; 0.97 g, 2.7 mmol) and pyridine (222 μL, 2.7 mmol) in Et₂O(2.7 mL) was added dropwise to the sulfuryl chloride solution over thecourse of 15 min. The flask was rinsed with Et₂O (2×20 mL), and therinse was added to the reaction mixture. The mixture was stirred at −78°C. for 10 min then allowed to warm to room temperature and stirred for 1h. The mixture was filtered, and the filtrate was concentrated undervacuum to afford the title compound (64b) as an oil, which was usedimmediately in the next step without further purification (not pure).

Step 3: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-3,3-dimethylbutyl2,6-dimethoxybenzoate (64)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.21 g, 1.1 mmol) was dissolved in THF (9.4 mL) and HMPA (0.5 mL),and the resulting stirred solution was cooled to −78° C. under an argonatmosphere. A solution of NaHMDS, 1.0 M in THF (1.1 mL, 1.1 mmol) wasadded to the mixture, and the mixture stirred for 10 min. A solution of4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl 2,6-dimethoxybenzoate (64b)(0.65 g, 1.7 mmol) in Et₂O (20 mL) was quickly added to the reactionmixture. After 10 min stirring at −78° C., the mixture was allowed towarm to room temperature and stirred for 1 h. The mixture was cooled to0° C. and quenched with H₂O and diluted with EtOAc. The aqueous andorganic layers were separated, and the organic layer was washed withbrine, dried (Na₂SO₄), and concentrated under vacuum. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 1:0) as eluent to give the product (64) (100 mg, 17%) as a solid.LCMS: m/z=530.01 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.31-7.25 (m, 1H),6.54 (d, J=9.0 Hz, 2H), 6.50 (br. s, 1H), 5.58 (br. s, 1H), 4.54 (d,J=8.7 Hz, 1H), 4.40 (t, J=6.8 Hz, 2H), 4.28 (d, J=8.7 Hz, 1H), 4.16 (br.s, 1H), 4.03 (d, J=6.9 Hz, 1H), 3.81 (s, 6H), 3.33 (d, J=11.7 Hz, 1H),2.99 (d, J=7.2 Hz, 1H), 2.44-2.39 (m, 1H), 2.21-2.13 (m, 1H), 1.93-1.79(m, 4H), 1.07 (s, 6H). ¹³C NMR (75 MHz, CDCl3): δ171.0, 167.1, 166.7,157.3, 131.2, 113.1, 103.9, 84.0, 62.0, 61.8, 60.2, 56.0, 47.2, 36.6,34.1, 23.8, 23.6, 20.8, 17.5.

Example 65 Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentylbenzoate (65)

Step 1: Synthesis of 5-hydroxy-4,4-dimethylpentyl benzoate (65a)

To a stirred solution of 2,2-dimethylpentane-1,5-diol (J. Org. Chem.2010, 75, 1892-1897; PCT International Publication No. WO 2002092606)(1.55 g, 11.7 mmol) in DCM (20 mL) at ca. 0° C. (ice bath) under anargon atmosphere, was added benzoyl chloride (1.5 mL, 12.9 mmol). Thereaction mixture was stirred at room temperature for 2.5 h andconcentrated under vacuum. EtOAc was added to the residue and themixture was stirred. The filtrate was concentrated under the residuepurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 1:4) as eluent to give the product (65a) (1.38 g, 50%) as an oil. ¹HNMR (300 MHz, CDCl₃): δ 8.04 (d, J=6.9 Hz, 2H), 7.56 (t, J=7.5 Hz, 1H),7.44 (t, J=7.5 Hz, 2H), 4.31 (t, J=6.8 Hz, 2H), 3.36 (s, 2H), 1.81-1.71(m, 2H), 1.42-1.36 (m, 2H), 0.92 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl benzoate(65b)

A solution of freshly distilled sulfuryl chloride (0.2 mL, 2.7 mmol) inEt₂O (1.9 mL) was cooled to −78° C. under an argon atmosphere. Asolution of 4-hydroxy-3,3-dimethylpentyl benzoate (65a) (0.76 g, 3.2mmol) and pyridine (218 μL, 2.7 mmol) in Et₂O (2.7 mL) was addeddropwise to the sulfuryl chloride solution over the course of 15 min.The flask was rinsed with Et₂O (2×20 mL), and the rinse was added to thereaction mixture. The mixture was stirred at −78° C. for 10 min thenallowed to warm to room temperature and stirred for 1 h. The mixture wasfiltered, and the filtrate was concentrated under vacuum to afford thetitle compound (65b) as an oil, which was used immediately in the nextstep without further purification (not pure). ¹H NMR (300 MHz, CDCl₃): δ8.04 (d, J=7.5 Hz, 2H), 7.57-7.55 (m, 1H), 7.48-7.33 (m, 1H), 4.35-4.29(m, 2H), 4.23 (s, 2H), 1.81-1.74 (m, 2H), 1.53-1.21 (m, 2H), 1.06 (s,6H).

Step 3: Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentylbenzoate (65)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.21 g, 1.1 mmol) was dissolved in THF (9.4 mL) and HMPA (0.5 mL),and the resulting stirred solution was cooled to −78° C. under an argonatmosphere. A solution of NaHMDS, 1.0 M in THF (1.1 mL, 1.1 mmol) wasadded to the mixture, and the mixture stirred for 10 min. A solution of5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl benzoate (65b) (0.42 g, 1.2mmol) in Et₂O (20 mL) was quickly added to the reaction mixture. After10 min stirring at −78° C., the mixture was allowed to warm to roomtemperature and stirred for 1 h. The mixture was cooled to 0° C. andquenched with H₂O and diluted with EtOAc. The aqueous and organic layerswere separated, and the organic layer was washed with brine, dried(Na₂SO₄), and concentrated under vacuum. The residue was purified bycolumn chromatography on silica gel using EtOAc/hexanes (0:1 to 7:3) aseluent to give the product (65) (160 mg, 29%) as a solid. LCMS:m/z=484.10 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 8.04 (d, J=7.5 Hz, 2H),7.57-7.54 (m, 1H), 7.47-7.42 (m, 2H), 6.43 (br. s, 1H), 5.51 (br. s,1H), 4.56 (d, J=9.0 Hz, 1H), 4.32-4.17 (m, 4H), 4.02 (d, J=7.2 Hz, 1H),3.28 (d, J=12.3 Hz, 1H), 2.97 (d, J=12.3 Hz, 1H), 2.44-2.40 (m, 1H),2.20-2.14 (m, 1H), 1.94-1.72 (m, 4H), 1.51-1.45 (m, 2H), 1.02 (s, 6H).¹³C NMR (75 MHz, CDCl₃): δ 171.0, 167.1, 166.8, 133.1, 130.4, 129.7,128.5, 83.6, 65.3, 61.9, 60.2, 47.2, 34.8, 34.3, 23.9, 23.6, 23.3, 20.8,17.5.

Example 66 Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethoxybenzoate (66)

Step 1: Synthesis of 5-hydroxy-4,4-dimethylpentyl 2,6-dimethoxybenzoate(66a)

To a stirred solution of 2,2-dimethylpentane-1,5-diol (1.5 g, 11.3 mmol)in pyridine (8.3 mL) at 0° C. under an argon atmosphere was added2,6-dimethoxybenzoyl chloride (80%; 1.4 g, 5.6 mmol) in one portion. Thereaction mixture was allowed to warm to room temperature and for 3 h.The reaction mixture was concentrated to dryness and EtOAc was added.The mixture was filtered and the filtrate was concentrated under vacuum.The residue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 3:7) as eluent to give the product (66a) (0.65 g,39%) as an oil. ¹H NMR (300 MHz, CDCl₃): δ 7.31-7.26 (m, 2H), 6.55 (d,J=8.1 Hz, 2H), 4.33 (t, J=6.2 Hz, 2H), 3.82 (s, 6H), 3.33 (s, 2H),1.77-1.67 (m, 2H), 1.41-1.35 (m, 2H), 0.92 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethoxybenzoate (66b)

A solution of freshly distilled sulfuryl chloride (0.16 mL, 2.2 mmol) inEt₂O was cooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-4,4-dimethylpentyl 2,6-dimethoxybenzoate (66a) (0.65 g, 2.2mmol) and pyridine (177 μL, 2.2 mmol) in Et₂O was added dropwise to thesulfuryl chloride solution over the course of 15 min. The flask wasrinsed with Et₂O (2×20 mL), and the rinse was added to the reactionmixture. The mixture was stirred at −78° C. for 10 min and then allowedto warm to room temperature and stirred for 1 h. The mixture wasfiltered, and the filtrate was concentrated under vacuum to afford thetitle compound (66b) as an oil, which was used immediately in the nextstep without further purification (not pure). ¹H NMR (300 MHz, CDCl₃): δ7.32-7.26 (m, 1H), 6.56 (d, J=8.7 Hz, 2H), 4.34 (t, J=6.2 Hz, 2H), 4.21(s, 2H), 3.81 (s, 6H), 1.77-1.71 (m, 2H), 1.52-1.46 (m, 2H), 1.03 (s,6H).

Step 3: Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethoxybenzoate (66)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.21 g, 1.1 mmol) was dissolved in THF (9.4 mL) and HMPA (0.5 mL),and the resulting stirred solution was cooled to −78° C. under anatmosphere of argon. A solution of NaHMDS, 1.0 M in THF (1.1 mL, 1.1mmol) was added to the mixture, and the mixture stirred for 10 min. Asolution of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethoxybenzoate (66b) (0.49 g, 1.2 mmol) in Et₂O (20 mL) wasquickly added to the reaction mixture. After 10 min stirring at −78° C.,the mixture was allowed to warm to room temperature and stirred for 1 h.The mixture was cooled to 0° C. and quenched with H₂O and diluted withEtOAc. The aqueous and organic layers were separated, and the organiclayer was washed with brine, dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 1:0) as eluent to give the product (66) (115mg, 18%) as a solid. LCMS: m/z=544.17 [M+H]⁺& 589.11 [M+HCOOH]⁺. ¹H NMR(300 MHz, CDCl₃): δ 7.31-7.25 (m, 1H), 6.55 (d, J=8.7 Hz, 2H), 6.51 (br.s, 1H), 5.51 (br. s, 1H), 4.53 (d, J=9.0 Hz, 1H), 4.33 (t, J=6.2 Hz,2H), 4.23-4.16 (m, 2H), 4.03 (d, J=7.5 Hz, 1H), 3.82 (s, 6H), 3.31 (d,J=12.3 Hz, 1H), 2.98 (d, J=11.7 Hz, 1H), 2.42-2.39 (m, 1H), 2.20-2.18(m, 1H), 2.00-1.68 (m, 4H), 1.49-1.44 (m, 2H), 1.00 (s, 6H). ¹³C NMR (75MHz, CDCl₃): δ 171.0, 167.0, 166.7, 157.4, 131.2, 110.1, 104.1, 83.9,65.6, 62.0, 60.2, 56.1, 47.2, 34.7, 34.3, 23.8, 23.6, 23.4, 20.8, 17.6.

Example 67 Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethylbenzoate (67)

Step 1: Synthesis of 5-hydroxy-3,3-dimethylpentyl 2,6-dimethylbenzoate(67a)

To a stirred solution of 2,2-dimethylpentane-1,5-diol (1.1 g, 8.3 mmol)in pyridine (8.3 mL) at 0° C. under an argon atmosphere was added2,6-dimethylbenzoyl chloride in one portion. The reaction mixture wasallowed to warm to room temperature for 3 h. The reaction wasconcentrated to dryness and EtOAc was added. The mixture was filteredand the filtrate was concentrated under vacuum. The residue was purifiedby column chromatography on silica gel using EtOAc/hexanes (0:1 to 1:4)as eluent to give the product (67a) (0.44 g, 25%) as an oil. ¹H NMR (300MHz, CDCl₃): δ 7.18 (t, J=7.7 Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4.32 (t,J=6.3 Hz, 2H), 3.34 (s, 2H), 2.32 (s, 6H), 1.78-1.68 (m, 2H), 1.40-1.34(m, 2H), 0.90 (s, 6H).

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethylbenzoate (67b)

A solution of freshly distilled sulfuryl chloride (122 μL, 1.7 mmol) inEt₂O was cooled to −78° C. under an atmosphere of argon. A solution of5-hydroxy-4,4-dimethylpentyl 2,6-dimethylbenzoate (67a) (0.44 g, 1.7mmol) and pyridine (135 μL, 1.7 mmol) in Et₂O was added dropwise to thesulfuryl chloride solution over the course of 15 min. The flask wasrinsed with Et₂O (2×20 mL), and the rinse was added to the reactionmixture. The mixture was stirred at −78° C. for 10 min and then allowedto warm to room temperature and stirred for 1 h. The mixture wasfiltered, and the filtrate was concentrated under vacuum to afford thetitle compound (67b), which was used immediately in the next stepwithout further purification. ¹H NMR (300 MHz, CDCl₃): δ 7.19 (t, J=7.5Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4.33 (t, J=6.2 Hz, 2H), 4.20 (s, 2H),2.32 (s, 6H), 1.81-1.71 (m, 2H), 1.51-1.45 (m, 2H), 1.04 (s, 6H).

Step 3: Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl2,6-dimethylbenzoate (67)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.21 g, 1.1 mmol) was dissolved in THF (9.4 mL) and HMPA (0.5 mL),and the resulting stirred solution was cooled to −78° C. under an argonatmosphere. A solution of NaHMDS, 1.0 M in THF (1.1 mL, 1.1 mmol) wasadded to the mixture, and the mixture stirred for 10 min. A solution of5-((chlorosulfonyl)oxy)-4,4-dimethylpentyl 2,6-dimethylbenzoate (67b)(0.49 g, 1.4 mmol) in Et₂O (20 mL) was quickly added to the reactionmixture. After 10 min stirring at −78° C., the mixture was allowed towarm to room temperature and stirred for 1 h. The mixture was cooled to0° C. and quenched with H₂O and diluted with EtOAc. The aqueous andorganic layers were separated, and the organic layer was washed withbrine, dried (Na₂SO₄), and concentrated under vacuum. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 7:3) as eluent to give the product (67) (200 mg, 32%) as a solid.LCMS: m/z=512.18 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.19 (t, J=7.5 Hz,1H), 7.03 (d, J=7.5 Hz, 2H), 6.45 (br. s, 1H), 5.52 (br. s, 1H), 4.54(d, J=9.3 Hz, 1H), 4.31 (t, J=7.4 Hz, 2H), 4.23-4.17 (m, 2H), 4.03 (d,J=7.2 Hz, 1H), 3.31 (d, J=11.7 Hz, 1H), 2.99 (d, J=12.3 Hz, 1H),2.45-2.40 (m, 1H), 2.32 (s, 6H), 2.18-2.14 (m, 1H), 1.98-1.70 (m, 4H),1.48-1.42 (m, 2H), 1.00 (s, 6H). ¹³C NMR (75 MHz, CDCl₃): δ 170.9,170.2, 167.1, 135.0, 134.1, 129.4, 127.7, 83.6, 65.4, 62.0, 60.2, 47.2,34.9, 34.3, 23.7, 23.6, 23.3, 20.8, 19.9, 17.5.

Example 68 Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.11]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl2-methylbenzoate (68)

Step 1: Synthesis of 4-hydroxy-3,3-dimethylbutyl 2-methylbenzoate (68a)

To a stirred solution of 2,2-dimethylbutane-1,4-diol (0.80 g, 6.8 mmol)in pyridine (5 mL) at ca. 0° C. (ice bath) under an argon atmosphere,was added toluoyl chloride (0.89 mL, 6.8 mmol) dropwise. The reactionmixture was allowed to gradually warm to room temperature and themixture was stirred for 4 h. The mixture was concentrated under vacuumand suspended in EtOAc, and then filtered and the filter cake washedwith EtOAc. The filtrate was concentrated under vacuum and the residuepurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 3:7) as eluent to give the desired product (68a) (0.7 g, 44%). ¹H NMR(300 MHz, CDCl₃): δ 7.88 (d, J=8.4 Hz, 1H), 7.40 (t, J=7.1 Hz, 1H),7.26-7.24 (m, 2H), 4.38 (t, J=7.3 Hz, 2H), 3.41 (s, 3H), 2.60 (s, 3H),1.78 (t, J=7.5 Hz, 2H), 0.98 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl2-methylbenzoate (68b)

A solution of freshly distilled sulfuryl chloride (96 μL, 1.3 mmol) inEt₂O (0.8 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 4-hydroxy-3,3-dimethylbutyl 2-methylbenzoate (68a) (0.31 g,1.3 mmol) and pyridine (106 μL, 1.3 mmol) in Et₂O (1.1 mL) was addeddropwise to the sulfuryl chloride solution over the course of 15 min.The flask was rinsed with Et₂O (2×20 mL), which was added to thereaction mixture. The mixture was stirred at −78° C. for 10 min thenallowed to warm to room temperature and stirred for 30 min. The mixturewas filtered, and the product (68b) was used immediately in the nextstep without further purification. ¹H NMR (300 MHz, CDCl₃): δ 7.89 (d,J=8.1 Hz, 1H), 7.41-7.39 (m, 1H), 7.26-7.25 (m, 2H), 4.41-4.35 (m, 2H),4.28 (s, 2H), 2.61 (s, 3H), 1.87 (t, J=7.2 Hz, 2H), 1.13 (s, 6H).

Step 3: Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-4,4-dimethylpentyl2-methylbenzoate (68)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.22 g, 1.2 mmol) was dissolved in THF (10 mL) and HMPA (0.5 mL),and the resulting stirred solution was cooled to −78° C. under anatmosphere of argon. A solution of NaHMDS, 1.0 M in THF (1.2 mL, 1.2mmol) was added to the mixture, and the mixture stirred for 10 min. Asolution of 4-((chlorosulfonyl)oxy)-3,3-dimethylbutyl 2-methylbenzoate(68b) (0.42 g, 1.3 mmol) in Et₂O (20 mL) was quickly added to thereaction mixture. After 10 min stirring at −78° C., the mixture wasallowed to warm to room temperature and stirred for 1 h. The mixture wascooled to 0° C. and quenched with H₂O and diluted with EtOAc. Theaqueous and organic layers were separated, and the organic layer waswashed with brine, dried (Na₂SO₄), and concentrated under vacuum. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 7:3) as eluent to give the product (68) (231 mg,40%) as a solid. LCMS: m/z=484.06 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ7.90 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.26-7.24 (m, 2H), 6.44(br. s, 1H), 5.53 (br. s, 1H), 4.60 (d, J=8.7 Hz, 1H), 4.35 (t, J=7.1Hz, 2H), 4.28 (d, J=9.0 Hz, 1H), 4.17 (br. s, 1H), 4.03 (d, J=7.2 Hz,1H), 3.33 (d, J=12.3 Hz, 1H), 2.99 (d, J=11.7 Hz, 1H), 2.60 (s, 3H),2.47-2.40 (m, 1H), 2.18-2.14 (m, 1H), 1.95-1.82 (m, 4H), 1.10 (s, 6H).¹³C NMR (75 MHz, CDCl₃): δ 171.0, 167.5, 167.1, 140.5, 132.2, 131.9,130.7, 129.5, 125.9, 83.7, 62.0, 61.2, 60.2, 47.2, 36.9, 34.0, 24.1,23.8, 21.9, 20.8, 17.5.

Example 69 Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl3-chloro-2,6-dimethoxybenzoate (69)

Step 1: Synthesis of 4-hydroxy-2,2,3,3-tetramethylbutyl2,6-dimethoxybenzoate (69a)

To a stirred solution of 2,2,3,3-tetramethylbutane-1,4-diol (45a) (0.7g, 4.8 mmol) in DCM (20 mL) at 0° C. under an atmosphere of argon wasadded 2,6-dimethoxybenzoyl chloride (80%; 0.55 g, 2.2 mmol), pyridine(0.36 mL, 4.4 mmol) and N,N-4-dimethylaminopyridine (0.05 g, 0.4 mmol).The mixture was allowed to warm to room temperature and stirred at roomtemperature overnight. The mixture was cooled to 0° C. and the reactionwas quenched by the addition of 1N HCl (15 mL), and then extracted withDCM (twice). The combined organic layers were washed with sat. sodiumbicarbonate and brine, then dried (Na₂SO₄), and concentrated undervacuum. The residue was purified by column chromatography on silica gelusing EtOAc/hexanes (0:1 to 3:2) as eluent to give the product (69a) asan oil. ¹H NMR (300 MHz, CDCl₃): δ 7.29 (t, J=8.4 Hz, 1H), 6.56 (d,J=8.1 Hz, 2H), 4.24 (s, 2H), 3.81 (s, 6H), 3.49 (s, 2H), 0.98 (s, 6H),0.92 (s, 6H).

Step 2: Synthesis of 4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl3-chloro-2,6-dimethoxybenzoate (69b)

Pyridine (0.15 mL, 1.8 mmol) was added to a stirred mixture of4-hydroxy-2,2,3,3-tetramethylbutyl propionate (69a) (0.30 g, 1.5 mmol)and Et₂O (10 mL) under an atmosphere of argon. The solution was cooledto −78° C. and sulfuryl chloride (0.15 mL, 1.8 mmol) in Et₂O (3 mL) wasslowly added at −78° C. The mixture was stirred at −78° C. for 1 h andthen warmed to room temperature, and stirred for 1 h. The reactionmixture was filtered to remove the pyridine salt, and the filtrate wasconcentrated under vacuum to give the title compound (69b) as an oil,that was used directly in the next step without further purification(yield assumed quantitative).

Step 3: Synthesis of4-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,3,3-tetramethylbutyl3-chloro-2,6-dimethoxybenzoate (69)

To a stirred mixture of(1R,2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (235 mg, 1.3 mmol) in THF (10 mL) under an atmosphere of argon wasadded several drops of 1,3-dimethyltetrahydropyrimidin-2(1H)-one. Themixture was cooled to −78° C. and stirred for 10 min, then a solution ofNaHMDS, 1.0M in THF (1.4 mL, 1.4 mmol) was added dropwise. The mixturewas stirred at −78° C. for 8 min, then4-((chlorosulfonyl)oxy)-2,2,3,3-tetramethylbutyl3-chloro-2,6-dimethoxybenzoate (69b) (0.52 g, 1.2 mmol) in THF (5 mL)was added at −78° C. The mixture was stirred at −78° C. for 10 min, thenallowed to warm to room temperature and stirred for 1 h. The mixture wasdiluted with EtOAc and saturated sodium bicarbonate solution. Theaqueous and organic layers were separated, and the organic layer waswashed with water, dried (Na₂SO₄), and concentrated under vacuum. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 1:0) as eluent to give the product (69) as asolid. ¹H NMR (300 MHz, CDCl₃): δ 7.33 (d, J=9.0 Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 6.51 (s, 1H), 5.74 (s, 1H), 4.75 (d, J=9.6 Hz, 1H), 4.44 (d,J=8.7 Hz, 1H), 4.22-4.15 (m, 3H), 4.02 (d, J=6.3 Hz, 1H), 3.88 (s, 3H),3.81 (s, 3H), 3.31 (d, J=11.7 Hz, 1H), 2.99 (d, J=12.3 Hz, 1H),2.43-2.39 (m, 1H), 2.16-2.12 (m, 1H), 1.91-1.80 (m, 2H), 1.05-1.01 (m,12H). ¹³C NMR (75 MHz, CDCl₃): δ 171.1, 167.1, 165.6, 156.0, 153.6,131.6, 120.1, 119.5, 107.8, 82.4, 71.2, 62.2, 61.9, 60.2, 56.2, 47.2,39.0, 38.7, 20.8, 20.7, 20.3, 20.2, 17.5.

Example 70 Synthesis of2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diyldibenzoate (70)

Step 1: Reaction to Produce 2-(hydroxymethyl)-2-methylpropane-1,3-diyldibenzoate (70a)

Benzoyl chloride (2.46 mL, 20.0 mmol) was added dropwise to a mixture of2-(hydroxymethyl)-2-methylpropane-1,3-diol (1.2 g, 10.0 mmol), pyridine(2.02 mL, 25.0 mmol), and N,N-4-dimethylaminopyridine (0.06 g, 0.4 mmol)in DCM (30 mL) at room temperature. After stirring at room temperatureovernight, the organic phase was washed with 1 M HCl, water, and brine,dried (MgSO₄), and concentrated under vacuum. The residue was purifiedby column chromatography on silica gel using EtOAc/hexanes (0:1 to 2:3)as eluent to give the product (70a) (1.3 g, 40%) as an oil. ¹H NMR (300MHz, CDCl₃): δ 8.06-8.02 (m, 4H), 7.62-7.56 (m, 2H), 7.49-7.42 (m, 4H),4.39 (s, 2H), 4.38 (s, 2H), 3.59 (s, 2H), 1.16 (s, 3H).

Step 2: Synthesis of2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl dibenzoate(70b)

A solution of freshly distilled sulfuryl chloride (0.3 mL, 3.7 mmol) inEt₂O (5 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 2-(hydroxymethyl)-2-methylpropane-1,3-diyl dibenzoate (70a)(800 mg, 2.4 mmol) and pyridine (0.32 mL, 3.9 mmol) in Et₂O (5 mL) wasadded dropwise to the sulfuryl chloride solution over the course of 5min. The flask was rinsed with Et₂O (3 mL), which was also added to themixture. The mixture was stirred at −78° C. for 1 h, and then allowed towarm to room temperature. The precipitate was filtered (quickly) and thefilter cake rinsed with Et₂O (12 mL). The filtrate was concentratedunder vacuum at room temperature to afford the title compound (70b) asan oil which was used immediately in the next step without furtherpurification.

Step 3: Synthesis of2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diyldibenzoate (70)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (400 mg, 2.2 mmol) was dissolved in THF (10 mL) and HMPA (1.1 mL),and the resulting solution was cooled to −78° C. under an argonatmosphere. A 1.0 M NaHMDS solution in THF (2.3 mL) was added dropwiseto the cooled solution and stirred for 10 min.2-(((Chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl dibenzoate(70b) (922 mg, 2.2 mmol) was dissolved in THF (8 mL) and was addedquickly to the reaction mixture. After stirring at −78° C. for 10 min,the reaction mixture was allowed to warm to room temperature. Afterstirring at room temperature for 2 h, EtOAc (400 mL) and saturatedaqueous NaHCO₃ (40 mL) and H₂O (40 mL) were added. The aqueous andorganic layers were separated, and the organic layer washed withsaturated aqueous NaHCO₃ (60 mL), water (3×50 mL), brine (60 mL), thendried (Na₂SO₄), and concentrated under vacuum. The residue was purifiedby column chromatography on silica gel using EtOAc/hexanes (0:1 to 1:9)as eluent to give the product (70) (186 mg, 15%) as an oil. LC-MS:m/z=576 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ 8.06-8.03 (m, 4H), 7.60-7.55(m, 2H), 7.44-7.26 (m, 4H), 6.41 (s, 1H), 5.49 (s, 1H), 4.97 (d, J=9.3Hz, 1H), 4.68 (d, J=9.3 Hz, 1H), 4.43-4.39 (m, 4H), 4.13 (m, 1H),4.01-3.99 (m, 1H), 3.13 (m, 1H), 2.95-2.91 (m, 1H), 2.45-2.40 (m, 1H),2.20-2.08 (m, 1H), 1.93-1.76 (m, 2H), 1.12 (s, 3H). ¹³C NMR (75 MHz,CDCl₃): δ 170.8, 167.1, 166.1, 133.3, 129.8, 129.7, 128.5, 77.2, 66.1,65.9, 61.8, 60.1, 46.9, 39.4, 20.6, 17.4, 16.9.

Example 71 Synthesis of2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diyldiacetate (71)

Step 1: Synthesis of 2-(hydroxymethyl)-2-methylpropane-1,3-diyldiacetate (71a)

Acetic anhydride (3.46 mL, 36.6 mmol) was added dropwise to a mixture of2-(hydroxymethyl)-2-methylpropane-1,3-diol (2.2 g, 18.0 mmol), pyridine(12 mL, 25.0 mmol), and N,N-4-dimethylaminopyridine (0.05 g) at roomtemperature. After stirring at room temperature overnight, the mixturewas concentrated under vacuum. The mixture was suspended in EtOAc (100mL), and H₂O (20 mL) was slowly added at 0° C. The aqueous and organiclayers were partitioned, and the organic layer was washed with andbrine, dried (Na₂SO₄), then concentrated under vacuum. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 3:2) as eluent to give the product (71a) (1.0 g, 26%). ¹H NMR (300MHz, CDCl₃): δ 4.02 (s, 4H), 3.41 (s, 2H), 2.08 (s, 6H), 0.96 (s, 3H).

Step 2: Synthesis of2-(((chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl diacetate (71b)

A solution of freshly distilled sulfuryl chloride (0.33 mL, 4.0 mmol) inEt₂O (4 mL) was cooled to −78° C. under an atmosphere of argon. Asolution of 2-(hydroxymethyl)-2-methylpropane-1,3-diyl diacetate (71a)(550 mg, 2.7 mmol) and pyridine (0.35 mL, 4.3 mmol) in Et₂O (4 mL) wasadded dropwise to the sulfuryl chloride solution over the course of 5min. The flask was rinsed with Et₂O (5 mL), which was also added to themixture. The mixture was stirred at −78° C. for 1 h, then allowed towarm to room temperature. The precipitate was filtered (quickly) and thefilter cake rinsed with Et₂O (12 mL). The filtrate was concentratedunder vacuum at room temperature to afford the title compound (71b) asan oil which was used immediately for the next step without furtherpurification.

Step 3: Synthesis of2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-methylpropane-1,3-diyldiacetate (71)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (430 mg, 2.3 mmol) was dissolved in THF (8 mL) and HMPA (0.8 mL),and the resulting solution was cooled to −78° C. under an atmosphere ofargon. NaHMDS, 1.0 M in THF (2.4 mL, 2.4 mmol) was added dropwise to thecooled solution and stirred for 10 min.2-(((Chlorosulfonyl)oxy)methyl)-2-methylpropane-1,3-diyl diacetate (71b)(703 mg, 2.3 mmol) was dissolved in THF (8 mL) and was added quickly tothe reaction mixture. After stirring at −78° C. for 10 min, the reactionmixture was allowed to warm to room temperature. After stirring at roomtemperature for 2 h, EtOAc (400 mL) and saturated aqueous NaHCO₃ (40 mL)and H₂O (40 mL) were added. The aqueous and organic layers wereseparated, and the organic layer washed with saturated aqueous NaHCO₃(60 mL), H₂O (3×50 mL), brine (60 mL), and then dried (Na₂SO₄), andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 1:9) as eluentto give the product (71) (198 mg, 19%) as an oil. LC-MS: m/z=452 [M+H]⁺.¹H NMR (300 MHz, CDCl₃): δ 6.50 (s, 1H), 5.68 (s, 1H), 4.72 (d, J=9.3Hz, 1H), 4.46 (d, J=9.3 Hz, 1H), 4.16 (m, 1H), 4.12-4.08 (m, 4H),3.36-3.32 (m, 1H), 3.04-3.00 (m, 1H), 2.45-2.40 (m, 1H), 2.20-2.12 (m,1H), 2.09 (s, 6H), 1.91-1.76 (m, 2H), 1.11 (s, 3H). ¹³C NMR (75 MHz,CDCl3): δ 171.1, 170.8, 170.7, 167.1, 76.9, 65.2, 61.9, 60.2, 47.1,38.8, 20.8, 20.7, 17.5, 16.6.

Example 72 Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl2,6-dimethoxybenzoate (72)

Step 1: Synthesis of 5-hydroxy-2,2,4,4-tetramethylpentyl2,6-dimethoxybenzoate (72a)

To a stirred solution of 2,2,4,4-tetramethylpentane-1,5-diol (39c) (0.64g, 4.0 mmol) and pyridine (0.32 mL, 4.0 mmol) in DCM (27 mL) was added2,6-dimethoxybenzoyl chloride (80%; 1.0 g, 4.0 mmol) in DCM (10 mL)dropwise over the course of 30 min at 0° C. (ice bath) under anatmosphere of argon. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. The mixture was diluted with H₂O (30mL), and the layers were separated. The aqueous layer was extracted withDCM (2×30 mL), and the combined organic layers were washed with brine(30 mL), dried (Na₂SO₄), and concentrated under vacuum. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 2:98) as eluent to give the product (72a) (927 mg, 71%) as an oil.The compound was contaminated, presumably with the diacylated byproduct.The material was used in the next step without further purification.

Step 2: Synthesis of 5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl2,6-dimethoxybenzoate (72b)

A solution of sulfuryl chloride (0.21 mL, 2.8 mmol) in Et₂O (13 mL) wascooled to −78° C. under an argon atmosphere. A solution of5-hydroxy-2,2,4,4-tetramethylpentyl 2,6-dimethoxybenzoate (72a) (921 mg,2.8 mmol) and pyridine (0.23 mL, 2.8 mmol) in Et₂O (13 mL) was addeddropwise to the sulfuryl chloride solution over the course of 10 min.The mixture was stirred at −78° C. for 5 h. The mixture was filtered andthe filtrate stored to give a solution of the product (72b) in Et₂O (ca.20 mL). The yield was assumed to be quantitative. This mixture was usedin the next step without further purification.

Step 3: Synthesis of5-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2,4,4-tetramethylpentyl2,6-dimethoxybenzoate (72)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (525 mg, 2.8 mmol) was dissolved in THF (33 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (4 mL) and the resultingsolution was cooled to −78° C. under an atmosphere of argon. A solutionof NaHMDS, 1.0 M in THF (2.8 mL, 2.8 mmol) was added dropwise to thecooled solution and stirred for 90 min. A solution of5-((chlorosulfonyl)oxy)-2,2,4,4-tetramethylpentyl 2,6-dimethoxybenzoate(72b) (1.2 g, 2.8 mmol) in Et₂O (ca. 20 mL) was added to the reactionmixture (cannula). After stirring for 10 min the mixture was warmed toroom temperature, and stirred for 2 h. The mixture was quenched with asaturated aqueous solution of sodium bicarbonate (40 mL) and extractedwith EtOAc (40 mL). The organic layer was washed with H₂O (3×40 mL),brine (40 mL), dried (Na₂SO₄), and concentrated under vacuum. Theresidue was purified by column chromatography on silica gel usingEtOAc/hexanes (2:3 to 9:1) as eluent to give the product (72) (726 mg,43%) as a solid. LC-MS: m/z=572.08 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃): δ7.32-7.26 (m, 1H), 6.56 (d, J=8.1 Hz, 2H), 6.52 (s, 1H), 5.64 (s, 1H),4.53 (d, J=8.7 Hz, 1H), 4.24 (d, J=9.0 Hz, 1H), 4.17 (s, 1H), 4.07-4.04(m, 3H), 3.81 (s, 6H), 3.34-3.30 (m, 1H), 3.00 (d, J=12.3 Hz, 1H),2.47-2.40 (m, 1H), 2.14 (m, 1H), 2.05-1.84 (m, 2H), 1.48 (s, 2H), 1.11(s, 6H), 1.10 (s, 6H). ¹³C NMR (75 MHz, CDCl₃): δ 171.0, 167.0, 166.8,157.5, 131.1, 113.3, 103.9, 85.2, 74.2, 61.9, 60.2, 56.0, 47.2, 46.1,36.0, 35.7, 26.4, 26.3, 25.9, 25.2, 20.8, 17.5.

Example 73 Synthesis of ethyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylbutanoate(73)

Step 1: Synthesis of R/S-ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylbutanoate (73a)

A solution of freshly distilled sulfuryl chloride (148 μL, 2.0 mmol) inEt₂O (0.2 mL) was cooled to −78° C. under an argon atmosphere. Asolution of ethyl 3-hydroxy-2,2-dimethylbutanoate (prepared according toJ. Med. Chem. 1987, 30, 366-374 and Ad. Synth. Catal. 2009, 351,3128-3132) (324 mg, 2.0 mmol) and pyridine (164 μL, 2.0 mmol) in Et₂O(0.2 mL) was added dropwise to the sulfuryl chloride solution over thecourse of 15 min. The flask was rinsed with Et₂O (2×20 mL), which wasadded to the reaction mixture. The mixture was stirred at −78° C. for 30min. The mixture was filtered and the product (73a) was used directly inthe next step with an assumed quantitative yield. ¹H NMR (300 MHz,CDCl₃): δ 5.34-5.29 (m, 1H), 4.22-4.14 (m, 2H), 1.55-1.52 (m, 3H),1.35-1.08 (min, 9H).

Step 2: Synthesis of ethyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylbutanoate(73)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.22 g, 1.2 mmol) was dissolved in THF (10 mL) and HMPA (0.5 mL),and the resulting stirred solution was cooled to −78° C. under anatmosphere of argon. A solution of NaHMDS, 1.0 M in THF (1.2 mL, 1.2mmol) was added to the mixture, and the mixture stirred for 10 min. Asolution of ethyl 3-((chlorosulfonyl)oxy)-2,2-dimethylbutanoate (73a)(0.51 g, 2.0 mmol) in Et₂O (20 mL) was added quickly to the reactionmixture. After 10 min stirring at −78° C., the mixture was allowed towarm to room temperature and stirred for 1 h. The mixture was cooled to0° C. and quenched with H₂O and diluted with EtOAc. The aqueous andorganic layers were separated, and the organic layer was washed withbrine, dried (Na₂SO₄), and concentrated under vacuum. The residue waspurified by column chromatography on silica gel using EtOAc/hexanes (0:1to 7:3) as eluent to give the product (73) (70 mg, 15%) as a solid. ¹HNMR (300 MHz, CDCl₃): δ 6.51 (br. s, 1H), 5.66 (br. s, 1H), 5.32 (q,J=6.3 Hz, 1H), 4.21-4.14 (m, 3H), 4.07 (t, J=6.3 Hz, 1H), 3.35-3.31 (m,1H), 3.04-2.98 (m, 1H), 2.44-2.39 (m, 1H), 2.17-2.09 (m, 1H), 1.95-1.83(m, 2H), 1.58-1.48 (m, 3H), 1.31-1.20 (m, 9H). ¹³C NMR (75 MHz, CDCl₃):δ 174.5, 174.4, 171.2, 171.1, 166.8, 166.6, 91.1, 90.6, 62.0, 62.0,61.5, 61.5, 60.2, 47.2, 47.2, 47.1, 21.2, 20.9, 20.8, 20.8, 20.6, 20.3,17.5, 17.5, 15.9, 15.5, 14.2 (Note: ¹³C NMR showed some duplicatedpeaks, due to a mixture of diastereomers).

Example 74 Synthesis of(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (74)

Step 1: Synthesis of 3,5,5-trimethyldihydrofuran-2(3H)-one (74a)

5,5-Dimethyldihydrofuran-2(3H)-one (4.7 g, 41.2 mmol) was dissolved inTHF (94 mL) and the mixture was cooled to −78° C. under an atmosphere ofargon. A solution of lithium diisopropylamide, 2.0 M solution in THF(22.6 mL, 45.2 mmol) was added dropwise over 10 min. The reaction wasstirred at −78° C. for 2 h, and then neat MeI (2.6 mL, 41.6 mmol) wasadded to the reaction over 5 min. The reaction was stirred at −78° C.for 45 min, and then the mixture was allowed to warm to room temperatureand stirred for 16 h. The reaction was quenched with saturated NH₄Cl (25mL) and the mixture concentrated to remove THF. The aqueous residue wasdiluted with H₂O to dissolve solid and then extracted with ethyl acetate(3×40 mL). The combined organic layer was concentrated under vacuum, andthe residue was purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 2:3) as eluent to provide a liquid whichsolidified on standing. This solid was purified further via Kugelrohrdistillation to give the product (74a) (3.2 g) as an oil. ¹H NMR (300MHz, CDCl₃): δ 2.78-2.87 (m, 1H), 2.33 (dd, J=9.3, 12.3 Hz, 1H), 1.71(t, J=12.3 Hz, 1H), 1.45 (s, 3H), 1.38 (s, 3H), 1.29 (d, J=6.9 Hz, 3H).

Step 2: Synthesis of3-((benzyloxy)methyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (74b)

3,5,5-Trimethyldihydrofuran-2(3H)-one (74a) (3.2 g, 25.0 mmol) wasdissolved in THF (60 mL) and the mixture was cooled to −78° C. under anatmosphere of argon. A solution of lithium diisopropylamide, 2.0 M inTHF (13.7 mL, 27.5 mmol) was added dropwise over 10 min. The mixture wasstirred at −78° C. for 30 min, then neat benzyl chloromethyl ether (90%;4.2 mL, 27.5 mmol) was added over 5 min. The mixture was allowed to warmto room temperature and was stirred for 16 h. Saturated NH₄Cl (10 mL)and H₂O (10 mL) was added and the solvent was removed under vacuum. Theresidue was extracted with EtOAc (2×75 mL) and the combined organiclayers were washed with brine (2×75 mL), dried (Na₂SO₄), filtered andconcentrated under vacuum (5.8 g). The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (0:1 to 2:3) as eluentto give the product (2.27 g) and impure fractions (1.35 g). The impurefractions were re-purified by column chromatography on silica gel usingEtOAc/hexanes (0:1 to 1:4) as eluent to give additional pure product(74b) (1.39 g). The product (3.66 g) was an oil. ¹H NMR (300 MHz,CDCl₃): δ 7.28-7.34 (m, 5H), 4.62 (dd, J=11.7, 35.1 Hz, 2H), 3.61 (d,J=11.7 Hz, 1H), 3.32 (d, J=11.7 Hz, 1H), 2.48 (d, J=12.9 Hz, 1H), 1.89(d, J=12.9 Hz, 1H), 1.45 (d, J=6.9 Hz, 6H), 1.26 (s, 3H).

Step 3: Synthesis of3-(hydroxymethyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (74c)

3-((Benzyloxy)methyl)-3,5,5-trimethyldihydrofuran-2(3H)-one (74b) (1.8g, 7.2 mmol) was dissolved in 2-propanol (60 mL) and the solution wasdegassed with argon. Solid 10.0% palladium on carbon (0.31 g, 0.3 mmol)was added to the flask. The flask was sealed and vacuum degassed, andthen back flushed with hydrogen (3 times). The reaction was stirred for6 h. The suspension was filtered through Celite® and the filter cakewashed with 2-propanol (15 mL). The filtrate was concentrated undervacuum to provide the product (74c) as a crude oil. ¹H NMR (300 MHz,CDCl₃): δ 3.75 (dd, J=6.9, 11.1 Hz, 1H), 3.51 (dd, J=5.7, 11.1 Hz, 1H),2.33 (d, J=12.9 Hz, 1H), 2.23 (t, J=6 Hz, 1H), 1.94 (d, J=12.9 Hz, 1H),1.48 (d, J=6.9 Hz, 6H), 1.32 (s, 3H).

Step 4: Synthesis of (3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methylsulfochloridate (74d)

A solution of 3-(hydroxymethyl)-3,5,5-trimethyldihydrofuran-2(3H)-one(74c) (0.50 g, 3.2 mmol) and pyridine (0.28 mL, 3.5 mmol) in Et₂O (10mL) was cooled to −78° C. under an atmosphere of argon. Neat sulfurylchloride (0.28 mL, 3.5 mmol) was added dropwise to the above solutionvia syringe. The mixture was stirred at −78° C. for 10 min, then theflask was warmed to room temperature and stirred for 1 h (monitored byTLC 30% EA/hexanes). A precipitate formed to give a thick suspension.The suspension was filtered through a 0.45-μM Teflon® filter and thefilter cake rinsed with fresh Et₂O (2×5 mL). An aliquot (0.5 mL) wastaken and concentrated and an NMR was obtained for the mixture. Theremaining solution containing the product (74d) was used directly in thenext step. ¹H NMR (300 MHz, CDCl₃): δ 4.60 (d, J=9.3 Hz, 1H), 4.36 (d,J=9.3 Hz, 1H), 2.37 (d, J=14.1 Hz, 1H), 2.09 (d, J=13.5 Hz, 1H), 1.51(d, J=8.4 Hz, 6H), 1.44 (s, 3H).

Step 5: Synthesis of(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (74)

(1R,2S,5R)-6-Hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide(1) (0.64 g, 3.5 mmol) was dissolved in THF (30 mL) and1,3-dimethyltetrahydropyrimidin-2(1H)-one (1.4 mL), and the resultingsolution was cooled to −78° C. under an argon atmosphere. NaHMDS, 1.0 Msolution in THF (3.5 mL, 3.5 mmol) was added dropwise to the cooledsolution and the mixture stirred for 1 h. A solution of(3,5,5-trimethyl-2-oxotetrahydrofuran-3-yl)methyl sulfochloridate (74d)(0.81 g, 3.2 mmol) in Et₂O from the previous reaction was added quicklyto the reaction mixture. The mixture was allowed to warm to roomtemperature and stirred overnight. Brine (100 mL) and EtOAc (100 mL)were added, and the aqueous and organic layers were separated. Theaqueous layer was extracted with EtOAc (2×100 mL) and the combinedorganic layers were washed with brine (3×100 mL), dried (Na₂SO₄), andconcentrated under vacuum. The residue was purified by columnchromatography on silica gel using EtOAc/hexanes (1:4 to 1:0) as eluentto give a solid (0.42 g). The solid was triturated with Et₂O (100 mL)for 16 h, filtered and the filter cake washed with fresh Et₂O (3×20 mL)to give the product (74) (0.28 g) as a solid. LC-MS: m/z=406 [M+H]⁺. ¹HNMR (300 MHz, CDCl₃): δ, 6.55 (br. d, J=44.7 Hz, 1H), 5.82 (br. s, 1H),4.86 (dd, J=9.3, 63.6 Hz, 1H), 4.55 (dd, J=9.3, 46.2 Hz, 1H), 4.03-4.16(m, 2H), 3.30-3.35 (m, 1H), 3.06 (dd, J=4.8, 12.3 Hz, 1H), 2.38-2.45 (m,2H), 2.10-2.20 (m, 1H), 1.8-2.04 (m, 3H), 1.48 (s, 3H), 1.477 (d, J=6.6Hz, 3H), 1.40 (d, J=4.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 177.3,177.0, 170.9, 170.8, 167.3, 167.0, 82.0, 81.9, 78.6, 77.8, 61.9, 60.2,60.2, 47.1, 46.9, 45.8, 45.7, 43.6, 43.2, 30.1, 29.8, 29.7, 22.5, 20.7,20.7, 17.4 (Note: ¹³C NMR showed some duplicated peaks, due to a mixtureof diastereomers).

Example 75 Synthesis of ethyl3-(((((1R,2S,5R)-2-carbamoyl-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(75)

(1R,2S,5R)-6-(Benzyloxy)-3-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide(1) (3.6 mg, 0.01 mmol) was dissolved in a mixed solvent(EtOAc/H₂O/EtOH: 0.22/0.34/0.11 mL), to which was added Et₃N (0.25 μL,0.002 mmol) and Pd/C (dry, 10%; 1.3 mg, 20 mol %) under N₂ at roomtemperature. A hydrogen balloon was placed on the reaction flask toreplace nitrogen. The reaction mixture was degassed under vacuum andrecharged with hydrogen (3 times). The mixture was stirred at roomtemperature for 5 h and monitored by LCMS. When the reaction wascomplete the mixture was diluted with EtOAc (2 mL) and washed withbrine. The organic phase was isolated and dried (Na₂SO₄), filtered andconcentrated under vacuum. The residue (4.3 mg, 0.02 mmol) was dissolvedin THF (0.4 mL) and cooled to −78° C. NaHMDS (1M in THF; 21.3 μL, 0.02mmol) was added dropwise. The reaction mixture was stirred at −78° C.for 20 min, and then ethyl3-((chlorosulfonyl)oxy)-2,2-dimethylpropanoate (7.8 mg, 0.03 mmol) wasadded. The reaction was stirred at −78° C. for 20 min and then slowlywarmed up to room temperature and stirred overnight (the reaction wasmonitored with LCMS). After the reaction was complete, EtOAc (5 mL) wasadded and the organic layer washed with saturated NaHCO₃, followed bybrine. The organic phase was isolated and dried (Na₂SO₄), and theproduct (75) concentrated under vacuum. LC/MS: m/z=406 [M+H]⁺

Example 76 Oral Bioavailability in Rats

A pharmacokinetic (PK) study was performed in three male Sprague-Dawley(SD) rats following intravenous (IV) and oral (PO) administrations ofavibactam at 2 mg/kg and test compounds at 10 mg/kg, respectively andavibactam measured in plasma.

Avibactam, was dissolved in phosphate buffered saline (PBS) (pH 7.5) at0.4 mg/mL for intravenous (IV) injection. Compounds for oraladministration were formulated in 10% ethanol/40% polyethylene glycol(PEG) 400/50% water for injection (WFI) (pH 6.5) at 1 mg/mL. The dosingvolumes were 5 mL/kg for IV and 10 mL/kg for PO. All aspects of thiswork including housing, experimentation, and animal disposal wereperformed in general accordance with the “Guide for the Care and Use ofLaboratory Animals: Eighth Edition” (National Academies Press,Washington, D.C., 2011); and Suckow et al., Ed. The Laboratory Rat. 2ndEdition. Academic Press. New York. 2005. Animals had access to standardlab diet and autoclaved tap water ad libitum.

Blood aliquots (300 μL to 400 μL) were collected from jugularvein-catheterized rats into tubes coated with lithium heparin at varioustimes. The tubes were mixed gently and kept on ice and then centrifugedat 2,500 rpm for 15 min at 4° C., within 1 h after collection. Foranimals in the control groups, blood was collected by cardiac punctureand the plasma was harvested and kept frozen at −70° C. until furtheranalysis. Beaudoin et al., Bioanalytical method validation for thesimultaneous determination of ceftazidime and avibactam in rat plasma.Bioanalysis. 2016 8:111-22.

Plasma samples were processed using acetonitrile precipitation andanalyzed by LC-MS/MS. A plasma calibration curve was generated withaliquots of drug-free plasma were spiked with the test substance at thespecified concentration levels. The spiked plasma samples were processedtogether with the unknown plasma samples using the same procedure. Theprocessed plasma samples were stored at −70° C. until receiving LC-MS/MSanalysis, at which time peak areas were recorded, and the concentrationsof the test substance in the unknown plasma samples were determinedusing the respective calibration curve. The reportable linear range ofthe assay was determined, along with the lower limit of quantitation(LLQ). Plots of plasma concentration of compound versus time areconstructed. The pharmacokinetic parameters of compound after IV and POdosing (AUC_(last), AUC_(INF), T_(1/2), T_(max), and C_(max)) areobtained from the non-compartmental analysis (NCA) of the plasma datausing WinNonlin. WinNonlin® Certara L.P. Pharsight, St. Louis, Mo.

In these tests, avibactam exhibited an oral bioavailability (% F) of1.2%, and compounds (3), (4), (10), (11), (12), (13), (14), (15), (16),(17), (18), and (19) exhibited an oral bioavailability (% F) greaterthan 10%. Also, compounds (36), (37), (42), (53), (57), (58), and (59)exhibited an oral bioavailability (% F) greater than 10%.

In these tests, relebactam exhibited an oral bioavailability (% F) of1.8%, and compounds (20), (22), (23), and (25) exhibited an oralbioavailability (% F) greater than 5%.

Example 77 Minimum Inhibitory Concentration

Minimum inhibitor concentration (MIC) values of the investigationalmonobactams and β-lactamase inhibitors were determined by brothmicrodilution susceptibility testing conducted in accordance withguidelines from the Clinical and Laboratory Standards Institute(Clinical and Laboratory Standards Institute (CLSI). Methods forDilution Antimicrobial Susceptibility Tests for Bacteria That GrowAerobically; Approved Standard-Tenth Edition. CLSI document M07-A10.CLSI, 950 West Valley Road, Suite 2500, Wayne, Pa. 19087-1898 USA, 2015;CLSI. Performance Standards for Antimicrobial Susceptibility Testing:Twenty-Sixth Informational Supplement. CLSI document M100-S26, CLSI, 950West Valley Road, Suite 2500, Wayne, Pa. 19087 USA, 2016) against apanel of bacterial strains expressing characterized β-lactamases thatconfer resistance to β-lactams. Zasowski et al., The β-Lactams StrikeBack: Ceftazidime-Avibactam. Pharmacotherapy, 2015 35:755-70; Levasseuret al., In vitro antibacterial activity of the ceftazidime-avibactamcombination against enterobacteriaceae, including strains withwell-characterized β-lactamases. Antimicrob Agents Chemother, 201559:1931-4. Compounds were stored as dry powder and stored at −20° C.prior to testing. These compounds and comparator drugs were solubilizedin the appropriate solvent on the day of the assay. All drugs weretested using a drug concentration range of 0.001 μg/mL to 64 μg/mL.β-lactamase inhibitors were tested at a constant concentration of 4μg/mL. Isolates were streaked onto appropriate media and incubatedovernight at 35° C. The MIC values were determined using cation-adjustedMueller Hinton broth (MHBII; BD, Sparks, Md.) in accordance with CLSIguidelines in 96-well format plates. MICs were recorded after 18 hincubation at 35° C. The MIC was read and recorded as the lowestconcentration of drug that inhibited visible growth of the organism.

Example 78 Oral Bioavailability in Dogs

The oral bioavailability of certain avibactam prodrugs provided by thepresent disclosure in dogs was evaluated.

Dosing formulations were prepared on the day of dosing. Intravenousformulations were prepared under aseptic conditions, sterile filtered,and brought to room temperature prior to dosing. The intravenousformulation included avibactam at a final concentration of 2.0 mg/mL inPBS at pH 7.5.

The oral dosing formulations had a final concentration of eitheravibactam or an avibactam prodrug of 2 mg/mL in a solution of 1 mLethanol, 4 mL PEG400, and 5 mL water for injection, with the pH adjustedto 7 with 1N NaOH.

The formulations were administered to male Beagle dogs weighing from 8kg to 410 kg. The animals were maintained in accordance with the Guidefor the Care and Use of Laboratory Animals, National Research Council,The National Academies Press, Washington, D C, 2011.

The dogs received either an IV bolus dose of 10 mg/kg, or a peroral doseof 20 mg/kg. The dose levels were selected to bridge the gap betweenprimary historical control data and the NHP study (American VeterinaryMedial Association. AVMA Guidelines on Euthanasia. 2013) to accuratelypredict the prodrug activity in humans. Intravenous administration wasinto the cephalic vein followed by a 0.5 mL flush with sterile saline.Oral administration via to the stomach using an 18-French catheterfollowed by a 15-mL flush with deionized water. Two dogs were used foreach arm of the study.

The plasma concentration of avibactam was measured at intervalsfollowing administration. Within 2 minutes of collection, 100 μL ofwhole blood was transferred to K₂EDTA tubes containing 300 μLacetonitrile. Each via with the blood/acetonitrile mixture was vortexedfor about 30 seconds and immediately frozen on dry ice and maintainedfrozen (−55° C. to −85° C.) until analysis. The avibactam concentrationwas determined using LC/MS/MS.

The area under the concentration vs. time curves (AUC) was calculatedusing the linear trapezoidal method with linear interpolation. Thepercent oral bioavailability (% F) of avibactam was determined bycomparing the AUC following oral administration with the AUC followingIV administration on a dose normalized basis.

Compounds (3), (13), and (15) exhibited an avibactam oralbioavailability in male Beagle dogs of greater than 50% F.

Example 79 Oral Bioavailability in Monkeys

The oral bioavailability of certain avibactam prodrugs provided by thepresent disclosure in male Cynomolgus monkeys was evaluated.

Dosing formulations were prepared on the day of dosing. Intravenousformulations were prepared under aseptic conditions, sterile filtered,and brought to room temperature prior to dosing. The intravenousformulation included avibactam at a final concentration of 2.0 mg/mL inPBS at pH 7.5.

The oral dosing formulations had a final concentration of eitheravibactam or an avibactam prodrug of 2 mg/mL in a solution of 1 mLethanol, 4 mL PEG400, and 5 mL water for injection, with the pH adjustedto 7 with 1N NaOH.

The formulations were administered to male Cynomolgus monkeys weighingfrom 2 kg to 4 kg. The animals were maintained in accordance with theGuide for the Care and Use of Laboratory Animals, National ResearchCouncil, The National Academies Press, Washington, D C, 2011.

The monkeys received either an IV bolus dose of 10 mg/kg, or a peroraldose of 20 mg/kg. The dosing levels were selected to mimictherapeutically effective systemic concentrations in humans. Intravenousadministration was into the saphenous vein. Oral administration was viaoral intubation via a flexible oral tube. Two monkeys were used for eacharm of the study.

The plasma concentration of avibactam was measured at intervalsfollowing administration. Within 2 minutes of collection, 100 μL ofwhole blood was transferred to K2EDTA tubes containing 300 μLacetonitrile. Each via with the blood/acetonitrile mixture was vortexedfor about 30 seconds and immediately frozen on dry ice and maintainedfrozen (−55° C. to −85° C.) until analysis. The avibactam concentrationwas determined using LC/MS/MS.

The area under the concentration vs. time curves (AUC) was calculatedusing the linear trapezoidal method with linear interpolation. Thepercent oral bioavailability (% F) of avibactam was determined bycomparing the AUC following oral administration with the AUC followingIV administration on a dose normalized basis.

Compounds (3), (13), and (15) exhibited an avibactam oralbioavailability in Cynomolgus monkeys of greater than 50% F.

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein, butmay be modified within the scope and equivalents thereof.

What is claimed is:
 1. A compound selected from: 2-methoxyethyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(15); oxetan-3-yl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(16); ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate(17); ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopentane-1-carboxylate(18); ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate(19); (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42);S-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (53); and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(59); or a pharmaceutically acceptable salt of any of the foregoing. 2.The compound of claim 1, wherein the compound is 2-methoxyethyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(15):

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, wherein the compound is oxetan-3-yl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(16):

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein the compound is ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclohexanecarboxylate(17):

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein the compound is ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclopentane-1-carboxylate(18):

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, wherein the compound is ethyl1-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)cyclobutanecarboxylate(19):

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein the compound is(1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl((3-methyl-2-oxotetrahydrofuran-3-yl)methyl) sulfate (42):

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, wherein the compound isS-(3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropyl)ethanethioate (53):

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, wherein the compound is (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate(59):

or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising the compound of claim 1 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable vehicle. 11.The pharmaceutical composition of claim 10, further comprising anantibiotic.
 12. The pharmaceutical composition of claim 11, wherein theantibiotic comprises a f-lactam antibiotic.
 13. The pharmaceuticalcomposition of claim 11, wherein the antibiotic comprises ceftibuten,amoxicillin, or a combination thereof.
 14. The pharmaceuticalcomposition of claim 10, wherein the pharmaceutical composition is anoral dosage formulation.
 15. A method of treating a bacterial infectionin a patient comprising administering to a patient in need of suchtreatment a therapeutically effective amount of the compound of claim 1or a pharmaceutically acceptable salt thereof; and a therapeuticallyeffective amount of a β-lactam antibiotic, wherein bacteria causing thebacterial infection produce a β-lactamase.
 16. The method of claim 15,wherein administering comprises orally administering.
 17. The method ofclaim 15, wherein the β-lactam antibiotic comprises ceftibuten,amoxicillin, or a combination thereof.
 18. A method of treating abacterial infection in a patient comprising administering to a patientin need of such treatment a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof, and atherapeutically effective amount of a β-lactam antibiotic, wherein thebacterial infection is capable of being treated with a therapeuticallyeffective amount of the β-lactam antibiotic when co-administered with atherapeutically effective amount of avibactam.
 19. The method of claim18, wherein administering comprises orally administering.
 20. The methodof claim 18, wherein the β-lactam antibiotic comprises ceftibuten,amoxicillin, or a combination thereof.
 21. A method of treating abacterial infection in a patient comprising administering to a patientin need of such treatment a therapeutically effective amount of thepharmaceutical composition of claim 10; and a therapeutically effectiveamount of a β-lactam antibiotic, wherein bacteria causing the bacterialinfection produce a β-lactamase.
 22. The method of claim 21, whereinadministering comprises orally administering.
 23. The method of claim21, wherein the β-lactam antibiotic comprises ceftibuten, amoxicillin,or a combination thereof.
 24. A method of treating a bacterial infectionin a patient comprising administering to a patient in need of suchtreatment a therapeutically effective amount of the pharmaceuticalcomposition of claim 10, and a therapeutically effective amount of aβ-lactam antibiotic, wherein the bacterial infection is capable of beingtreated with a therapeutically effective amount of the β-lactamantibiotic when co-administered with a therapeutically effective amountof avibactam.
 25. The method of claim 24, wherein administeringcomprises orally administering.
 26. The method of claim 24, wherein theβ-lactam antibiotic comprises ceftibuten, amoxicillin, or a combinationthereof.